A3 adenosine receptor antagonists

ABSTRACT

Disclosed are pyridine and dihydropyridine derivatives, pharmaceutical compositions comprising one or more of these derivatives, and a method of selectively blocking an A 3  adenosine receptor of a mammal by the use of one or more of these derivatives. An example of the pyridine derivative is of the formula (I):                    
     wherein R 2  is ethyl, R 3  is ethylsulfanyl; R 4  is ethyl, propyl, or hydroxypropyl; R 5  is ethyl, propyl, fluoroethyl, or fluoropropyl; and R 6  is phenyl or fluorophenyl. The derivatives of the present invention can be used for inhibiting binding of ligands to an adenosine receptor. The derivatives also can be used for characterizing an adenosine receptor.

This application is a 371 of PCT/US99/15562 filed Jul. 2, 1999, now WO 00/02851, which claims the benefit of Ser. No. 60/092,292 filed Jul. 10, 1998.

TECHNICAL FIELD OF THE INVENTION

The present invention relates to certain novel A₃ adenosine receptor antagonists, pharmaceutical compositions, and methods of selectively blocking A₃ adenosine receptors in a mammal. The present invention also relates to methods of preventing or treating various medical disorders or conditions with the adenosine receptor antagonists.

BACKGROUND OF THE INVENTION

The use of caffeine and other alkylxanthines as physiological stimulants is well known. The principle mechanism by which caffeine and other alkylxanthines act as physiological stimulants is by blocking the effects of the ubiquitous neuromodulator adenosine. Daly, “Mechanism of Action of Caffeine”, in Caffeine, Coffee and Health, (S. Garattini, Ed.), Chapter 4, pp. 97-150 (1993). Adenosine is produced locally in response to increased activity or stress to the system. This feedback mechanism allows the organ to compensate for the stress by decreasing energy demand (depressant activity) and increasing oxygen supply (e.g., by vasodilation). Bruns, Nucleosides & Nucleotides, 10, 931-944 (1991).

Adenosine plays several key physiological roles. In addition to its role in intermediary metabolism, adenosine displays a number of receptor-mediated physiological actions, including dilation of coronary vessels, inhibition of platelet aggregation, and inhibition of lipolysis. Bruns et al., Proc. Nat. Acad. Sci. U.S.A., 77, 5547-5551 (1980). Adenosine receptors, A₁, A₂, and A₃, belong to the G protein-coupled superfamily characterized by seven transmembrane helical domains. Several antagonists have been reported for these receptors in the literature. See, for example, Jacobson et al., “Development Of Selective Purinoceptor Agonists And Antagonists”, in Purinergic Approaches In Experimental Therapeutics, K. A. Jacobson and M. F. Jarvis, Ed, Wiley, Ch. 6, pp. 101-128 (1997). The pharmacology of the A₃ receptor is unique within the class of adenosine receptors. Zhou et al., Proc. Natl. Acad. Sci. USA, 89, 7432-7436 (1992).

The distribution of the A₃ receptor is found primarily in the central nervous system (CNS), brain, testes, and immune system, where it appears to be involved in the modulation of release from mast cells of mediators of the immediate hypersensitivity reaction. Ramkumar et al., J. Biol. Chem., 268, 16887-16890 (1993). It is believed that A₃-selective compounds will have utility in the therapeutic and/or prophylactic treatment of cardiac disease, infertility, kidney disease, and CNS disorders. Activation of the A₃ receptor has been linked to several second messenger systems such as stimulation of phospholipidases C and D and inhibition of adenylyl cyclase. Ali et al., J. Pharmacol. Exp. Therap., 276, 837-845 (1996).

Antagonists for the A₃ receptor are sought as potential anti-inflammatory, antiasthmatic, and antiischemic agents. von Lubitz et al., Eur. J. Pharmacol., 263, 59-67 (1994); Soc. For Neurosciences, Abstr. 745.16, 23, 1924 (1997). Some promising leads for A₃ adenosine receptor antagonists have been identified in certain 1,4-dihydropyridines, triazoloquinazolines, flavonoids, a triazolonaphthyridine, and a thiazolopyrimidine. Van Rhee et al., J. Med. Chem., 39, 2980-2989 (1996); Jiang et al., J. Med. Chem., 39, 4667-4675 (1996); Jiang et al., J. Med. Chem., 40, 2596-2608 (1997); Kim et al., J. Med. Chem., 39, 4142-4148 (1996); Karton et al., J. Med. Chem., 39, 2293-2301 (1996); Jacobson et al., Drug Devel. Res., 37, 131 (1996). WO 97/27177 discloses certain dihydropyrdines, pyridines, flavonoids, and triazoloquinazolines as possible A₃ adenosine receptor antagonists. Li et al., J. Med. Chem., 41, 3186-3201 (1998) discloses certain pyridine derivatives as possible A₃ adenosine receptor antagonists.

Thus, there remains a need for antagonists for A₃ adenosine receptors. The present invention seeks to provide such compounds, as well as methods of using these compounds to selectively block adenosine receptors in mammals, and pharmaceutical compositions comprising such compounds. These and other objects and advantages of the present invention, as well as additional inventive features, will be apparent from the description of the invention provided herein.

SUMMARY OF THE INVENTION

The present invention provides compounds of formula (I)

wherein R₂ is selected from the group consisting of C₁-C₆ alkyl, C₃-C₇ cycloalkyl, and C₁-C₆ alkoxy C₁-C₆ alkyl; R₃ is selected from the group consisting of C₁-C₆ alkoxy, C₁-C₆ alkylsulfanyl, hydroxy, C₁-C₆ alkoxy C₁-C₆ alkylsulfanyl, hydroxy C₁-C₆ alkylsulfanyl, and halo C₁-C₆ alkylsulfanyl, or R₃ together with R₄ forms a 3-7 membered heterocyclic ring containing O, N, or S; R₄ is selected from the group consisting of C₁-C₆ alkyl, halo C₁-C₆ alkyl, hydroxy C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆alkylsulfanyl, C₁-C₆ alkylamino, C₁-C₆ alkylcarbonyl sulfanyl C₁-C₆ alkyl, aryl C₂-C₆ alkenyl, aryl C₂-C₆ alkynyl, formyl, and acetal; R₅ is selected from the group consisting of C₁-C₆ alkyl, aryl C₁-C₆ alkyl, hydroxy C₁-C₆ alkyl, and halo C₁-C₆ alkyl; and R₆ is selected from the group consisting of aryl, C₃-C₇ cycloalkyl, and haloaryl; wherein the aryl is a phenyl or naphthyl; or a pharmaceutically acceptable salt thereof.

The present invention further provides compounds of formula (II)

wherein R₂ is a C₁-C₆ alkyl; R₃ is selected from the group consisting of C₁-C₆ alkoxy, C₁-C₆ alkoxy C₁-C₆ alkylsulfanyl, and C₁-C₆ alkylsulfanyl; R₄ is selected from the group consisting of C₁-C₆ alkyl, acetal, formyl, aryl C₂-C₆ alkenyl, and aryl C₂-C₆ alkynyl; R₅ is selected from the group consisting of C₁-C₆ alkyl and aryl C₁-C₆ alkyl; and R₆ is selected from the group consisting of aryl and C₃-C₆ cycloalkyl; wherein said aryl is a phenyl or naphthyl; or a pharmaceutically acceptable salt thereof.

The present invention further provides pharmaceutical compositions comprising any of the aforesaid compounds and a method of treating a mammal comprising selectively blocking one or more of the adenosine receptors, particularly the A₃ adenosine receptors, of the mammal by administering to the mammal at least one compound of formulas I and II.

The present invention further provides a method of characterizing an adenosine receptor, particularly an A₃ receptor, in a substrate comprising contacting said substrate with a compound of the present invention and evaluating the interaction of the compound with the adenosine receptor.

The present invention further provides a method of inhibiting the binding of a ligand to an adenosine receptor, particularly an A₃ receptor, of a substrate comprising contacting the substrate with a compound of the present invention so that the compound binds to the adenosine receptor and inhibits the ligand from binding to the adenosine receptor.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts a method of synthesis of dihydropyridine derivatives 60-66. and 74-76, starting from a β-enaminoester (77a-c), an aldehyde (78a-e), and a β-ketoester (79a-g).

FIG. 2 depicts a method of synthesis of dihydropyridine derivatives 70-73, starting from a β-enaminoester (77c), an aldehyde (78e), and a β-ketoester (79h-k).

FIG. 3 depicts a method of synthesis of a dihydropyridine derivative containing an aldehyde group (67) from a dihydropyridine derivative containing an acetal (66).

FIG. 4 depicts a method of synthesis of pyridine derivatives 34-41, 44, 46-48, and 55, starting from dihydropyridine derivatives 60-67, 71, 72, and 74-76.

FIG. 5 depicts a method of synthesis of pyridine derivatives 49a, 49b, 50-54, and 56-58, starting from a β-enaminoester (77a, and 77d-h), an aldehyde (78b), and a β-ketoester (79e, 79g, and 79l-n)

FIG. 6 depicts a method of synthesis of β-enaminoesters 77a, 77b, and 77d-h.

FIG. 7 depicts a method of synthesis of 2, 2-dimethoxy acetaldehyde (78d).

FIG. 8 depicts a method of synthesis of β-ketoesters 79c, 79d, and 79g.

FIG. 9 depicts a method of synthesis of β-ketoesters 79j and 79k.

FIG. 10 depicts a method of synthesis of β-ketoester 79u.

FIG. 11 depicts a method of synthesis of β-ketoesters 79e, 79f, 79h, 79i, 79l-n, and 79p-t.

FIG. 12 depicts the formulas of pyridine derivatives 29-32.

FIG. 13 depicts a method of synthesis of pyriding derivatives 3 and 29.

FIG. 14 depicts a method of synthesis of the pyridine derivative 30 and the N-1 methyl pyridinium salt of pyridine derivative 28.

FIG. 15 depicts a method of synthesis of pyrdine derivatives 31-32.

FIG. 16 depicts a method of synthesis of pyridine derivatives 8 and 10.

FIG. 17 depicts a method of synthesis of pyridine derivative 16.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The present invention may be best understood with reference to the accompanying drawings and to the following detailed description of the preferred embodiments. The present invention provides compounds of formula (I)

wherein R₂ is selected from the group consisting of C₁-C₆ alkyl, C₃-C₇ cycloalkyl, and C₁-C₆ alkoxy C₁-C₆ alkyl; R₃ is selected from the group consisting of C₁-C₆ alkoxy, C₁-C₆ alkylsulfanyl, hydroxy, C₁-C₆ alkoxy C₁-C₆ alkylsulfanyl, hydroxy C₁-C₆ alkylsulfanyl, and halo C₁-C₆ alkylsulfanyl, or R₃ together with R₄ forms a 3-7 membered heterocyclic ring containing O, N, or S; R₄ is selected from the group consisting of C₁-C₆ alkyl, halo C₁-C₆ alkyl, hydroxy C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ alkysulfanyl, C₁-C₆ alkylamino, C₁-C₆ alkylcarbonyl sulfanyl C₁-C₆ alkyl, aryl C₂-C₆ alkenyl, aryl C₂-C₆ alkynyl, formyl, and acetal; R₅ is selected from the group consisting of C₁-C₆ alkyl, aryl C₁-C₆ alkyl, hydroxy C₁-C₆ alkyl, and halo C₁-C₆ alkyl; and R₆ is selected from the group consisting of aryl, C₃-C₇ cycloalkyl, and haloaryl; wherein the aryl is a phenyl or naphthyl. The nitrogen atom of the heterocyclic ring can be saturated or unsaturated: Thus, for example, the heterocyclic ring can contain an NH group or an NR group wherein R is a C₁-C₆ alkyl, aryl, formyl, or C₁-C₆ acyl.

Among the compounds of formula (I), preferred embodiments include those wherein R₂ is selected from the group consisting of C₁-C₆ alkyl, C₃-C₇ cycloalkyl, and C₁-C₆ alkoxy C₁-C₆ alkyl; R₃ is selected from the group consisting of C₁-C₆ alkylsulfanyl, hydroxy, C₁-C₆ alkoxy C₁-C₆ alkylsulfanyl, hydroxy C₁-C₆ alkylsulfanyl, and halo C₁-C₆ alkylsulfanyl, or R₃ together with R₄ forms a 3-7 membered heterocyclic ring containing O, N, or S; R₄ is selected from the group consisting of C₁-C₆ alkyl, halo C₁-C₆ alkyl, hydroxy C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ alkylsulfanyl, C₁-C₆ alkylamino, C₁-C₆ alkylcarbonyl sulfanyl C₁-C₆ alkyl, aryl C₂-C₆ alkenyl, aryl C₂-C₆ alkynyl, formyl and acetal; R₅ is selected from the group consisting of C₁-C₆ alkyl, aryl C₁-C₆ alkyl, hydroxy C₁-C₆ alkyl and halo C₁-C₆ alkyl; and R₆ is selected from the group consisting of aryl, C₃-C₇ cycloalkyl and haloaryl; wherein the aryl is a phenyl or naphthyl.

Further preferred embodiments the compounds of formula (I) include those wherein R₂ is selected from the group consisting of C₁-C₄ alkyl, C₄-C₅ cycloalkyl, and C₁-C₃ alkoxy C₁-C₃ alkyl; R₃ is selected from the group consisting of C₁-C₆ alkylsulfanyl, hydroxy C₁-C₃ alkylsulfanyl and halo C₁-C₃ alkylsulfanyl; R₄ is selected from the group consisting of C₁-C₃ alkyl and hydroxy C₁-C₃ alkyl; R₅ is selected from the group consisting of C₁-C₃ alkyl and halo C₁-C₃ alkyl; and R₆ is selected from the group consisting of C₄-C₆ cycloalkyl, phenyl, and halophenyl. Particular embodiments of preferred compounds include those wherein R₂ is ethyl; R₃ is selected from the group consisting of C₁-C₆ alkylsulfanyl, hydroxy C₁-C₂ alkylsulfanyl, and halo C₁-C₂ alkylsulfanyl; R₄ is selected from the group consisting of C₁-C₃ alkyl and hydroxy C₁-C₃ alkyl; R₅ is selected from the group consisting of C₁-C₃ alkyl and halo C₁-C₃ alkyl; and R₆ is selected from the group consisting of phenyl and chlorophenyl.

Other embodiments of preferred compounds of formula (I) include those wherein R₂ is ethyl; R₃ is selected from the group consisting of ethylsulfanyl, hexylsulfanyl, haloethylsulfanyl, and hydroxyethyl sulfanyl; R₄ is selected from the group consisting of ethyl, propyl, and hydroxypropyl; R₅ is selected from the group consisting of ethyl, propyl, fluoroethyl, and fluoropropyl; and R₆ is selected from the group consisting of phenyl and halophenyl. Certain specific embodiments of preferred compounds include those wherein R₂ is ethyl; R₃ is ethylsulfanyl; R₄ is selected from the group consisting of ethyl, propyl, and hydroxypropyl; R₅ is selected from the group consisting of ethyl, propyl, fluoroethyl, and fluoropropyl; and R₆is phenyl or fluorophenyl.

Some specific examples of preferred compounds of formula (I) include 5-ethyl 2,4-diethyl 3-(ethylsulfanylcarbonyl)-6-phenylpyridine-5-carboxylate, 5-(2-fluoroethyl)-2,4diethyl-3-(ethysulfanylcarbonyl)-6-phenylpyrdine-5-carboxylate, 5-n-propyl 2,4-diethyl-3-(ethylsulfanylcaronyl)-6-phenylpyridine-5-carboxylate, 5-n-propyl 2-ethyl-4-n-propyl-3-(ethylsulfanylcarbonyl)-6-phenylpyridine-5-carboxylate, 5-n-propyl-2-ethyl-4-(3-hydroxy-n-propyl)-3(ethylsulfanylcarbonyl)-6-phenylpyridine-5-carboxylate, 5-(3-fluoro-n-propyl) 2-ethyl-4-n-propyl-3-(ethylsulfanylcarbonyl)-6-phenylpyridine-5-carboxylate, 5-n-propyl 2-ethyl-4-n-propyl-3-(ethylsulfanylcarbonyl)-6-(2-fluorophenyl)pyridine-5-carboxylate, 5-n-propyl 2-ethyl-4-n-propyl-3-(ethylsulfanylcarbonyl)-6-(3-fluorophenyl)pyridine-5-carboxylate, and 5-n-propyl 2-ethyl-4-n-propyl-3-(ethylsulfanylcarbonyl)-6-(4-fluorophenyl)pyridine-5-carboxylate.

Additional embodiments of preferred compounds of formula (I) include those wherein R₂ is ethyl; R₃ is selected from the group consisting of hexylsulfanyl, haloethylsulfanyl and hydroxyethylsulfanyl; R₄ is selected from the group consisting of ethyl and propyl; R₅ is propyl; and R₆ is phenyl. Thus, examples of such compounds include 5-n-propyl 2,4-diethyl-3-(n-hexylsulfanylcarbonyl)-6-phenylpyridine-5-carboxylate, 5-n-propyl 2-ethyl-4-n-propyl-3-(2-hydroxyethylsulfanylcarbonyl)-6-phenylpyridine-5-carboxylate, 5-n-propyl 2-ethyl-4n-propyl-3-(2-fluoroethylsulfanylcarbonyl)-6-phenylpyridine-5-carboxylate, and 5-n-propyl 2-ethyl-4-n-propyl-3-(2,2,2-trifluoroethylsulfanylcarbonyl)-6-phenylpyridine-5-carboxylate.

Further embodiments of preferred compounds of formula (I) include those wherein R₂ is methyl; R₃ is selected from the group consisting of C₁-C₃ alkoxy, ethylsulfanyl, and methoxyethylsulfanyl; R₄ is selected from the group consisting of C₁-C₃ alkyl and phenylethynyl; R₅ is selected from the group consisting ethyl and benzyl; and R₆ is selected from the group consisting of phenyl and C₄-C₅ cycloalkyl. Thus, examples of such preferred compounds include 3-n-propyl 5-ethyl-2,4-dimethyl-6-phenylpyridine-3,5-dicarboxylate, 3,5-diethyl 2-methyl-4-ethyl-6-phenylpyridine-3,5-dicarboxylate, 5-ethyl 2-methyl-4ethyl-3-(ethylsulfanylcarbonyl)-6-phenylpyridine-5-carboxylate, 5-ethyl 2-methyl-4-n-propyl-3(ethylsulfanylcarbonyl)-6-phenylpyridine-5-carboxylate, 5-benzyl 2-methyl-4-ethyl-3-(ethylsulfanylcarbonyl)-6-phenylpyridine-5-carboxylate, 3-ethyl 5-benzyl-2-methyl-4-phenylethynyl-6-cyclobutylpyridine-3,5-dicarboxylate, and 3-ethyl 5-benzyl-2-methyl-4-phenylethynyl-6-cyclopentylpyridine-3,5-dicarboxylate,

Certain other embodiments of preferred compounds of formula (I) include those wherein R₂ is selected from the group consisting of ethyl, propyl, butyl, cyclobutyl, and methoxyethyl; R₃ is selected from the group consisting of ethylsulfanyl, and propylsulfanyl; R₄ is selected from the group consisting of methyl, ethyl, and propyl; R₅ is selected from the group consisting of ethyl, propyl, and hydroxyethyl; and R₆ is selected from the group consisting of phenyl, chlorophenyl, and cyclopentyl. Thus, specific examples of such compounds include 3,5-diethyl 2-ethyl-4-methyl-(3-ethylsulfanylcarbonyl)-6-phenylpyridine-3,5-dicarboxylate, 5-ethyl 2,4-diethyl-3-(ethylsulfanylcarbonyl)-6-phenylpyridine-5-carboxylate, 5-propyl 2,4-diethyl-3-(ethylsulfanylcarbonyl)-6-phenylpyridine-5-carboxylate, 5-propyl 2-ethyl-4-propyl-3-(ethylsulfanylcarbonyl)-6-phenylpyridine-5-carboxylate, 5-hydroxylethyl 2,4-diethyl-3-(ethylsulfanylcarbonyl)-6-phenylpyridine-5-carboxylate, 5-ethyl 2,4-diethyl-3-(ethylsulfanylcarbonyl)-6-(m-chlorophenyl)pyridine-5-carboxylate, 5-ethyl 2,4diethyl-3(ethylsulfanylcarbonyl)-6-cyclopentylpyridine-5-carboxylate, 5-ethyl 2,4diethyl-3-(propylsulfanylcarbonyl)-7-phenylpyridine-5-carboxylate, 5-propyl 2,4diethyl-3-(propylsulfanylcarbonyl)-6-(m-chlorophenyl)pyridine-5-carboxylate, 5-ethyl 2-propyl-4-ethyl-3-(ethylsulfanylcarbonyl)-6-phenylpyridine-5-carboxylate, 5-ethyl 2-(2-methoxyethyl)-4-ethyl-3-(ethylsulfanylcarbonyl)-6-phenylpyridine-5-carboxylate, 5-ethyl 2-butyl-4-ethyl-3-(ethylsulfanylcarbonyl)-6-phenylpyridine-5-carboxylate, and 5-ethyl 2-cyclobutyl-4-ethyl-3-(ethylsulfanylcarbonyl)-6-phenylpyride-5-carboxylate.

The present invention further provides compounds of formula (II)

wherein R₂ is a C₁-C₆ alkyl; R₃ is selected from the group consisting of C₁-C₆ alkoxy, C₁-C₆ alkoxy C₁-C₆ alkylsulfanyl, and C₁-C₆ alkylsulfanyl; R₄ is selected from the group consisting of C₁-C₆ alkyl, acetal, formyl, aryl C₂-C₆ alkenyl, and aryl C₂-C₆ alkynyl; R₅ is selected from the group consisting of C₁-C₆ alkyl and aryl C₁-C₆ alkyl; and R₆ is selected from the group consisting of aryl and C₃-C₆ cycloalkyl; wherein said aryl is a phenyl or naphthyl. These compounds can be in the R or S form, or mixtures thereof.

Preferred embodiments of compounds of formula (II) include those wherein R₂ is a C₁-C₆ alkyl; R₃ is selected from the group consisting of C₁-C₆ alkoxy, C₁-C₆ alkoxy C₁-C₆ alkylsulfanyl, and C₁-C₆ alkylsulfanyl; R₄ is selected from the group consisting of C₁-C₆ alkyl, acetal, formyl, aryl C₂-C₆ alkenyl, and aryl C₂-C₆ alkynyl; R₅ is selected from the group consisting of C₁-C₆ alkyl and aryl C₁-C₆ alkyl; and R₆ is C₃-C₆ cycloalkyl. Examples of such compounds include 3-ethyl 5-benzyl 2-methyl-4-phenylethynyl-6-cyclopropyl-1,4-(±)-dihydropyridine-3,5-dicarboxylate, 3-ethyl 5-benzyl 2-methyl-4-phenylethynyl-6-cyclobutyl-1,4-(±)-dihydropyridine-3,5-dicarboxylate, 3-ethyl 5-benzyl 2-methyl-4-phenylethynyl-6-cyclopentyl-1,4-(±)-dihydropyridine-3,5-dicarboxylate, and 3-ethyl 5 benzyl 2-methyl-4 phenylethynyl-6-cyclohexyl-1,4-(±)-dihydropyridine-3,5-dicarboxylate.

Other preferred embodiments of the compounds of formula (II) include those wherein R₂ is a C₁-C₆ alkyl; R₃ is selected from the group consisting of C₁-C₆ alkoxy, C₁-C₆ alkoxy C₁-C₆ alkylsulfanyl, and C₁-C₆ alkylsulfanyl; R₄ is selected from the group consisting of C₁-C₆ alkyl, acetal, formyl, aryl C₂-C₆ alkenyl, and aryl C₂-C₆ alkynyl; R₅ is selected from the group consisting of C₁-C₆ alkyl and aryl C₁-C₆ alkyl; and R₆ is phenyl. Examples of such compounds include 3,5-diethyl 2, 4-dimethyl-6-phenyl-1,4-(±)-dihydropyridine-3,5-dicarboxylate, 3-propyl 5-ethyl-2,4-dimethyl-6-phenyl-1,4-(±)-dihydropyridine-3,5-dicarboxylate, 3,5-diethyl 2-methyl-4-ethyl-6-phenyl-1,4-(±)-dihydropyridine-3,5-dicarboxylate, 5-ethyl 2-methyl-4-ethyl-6-phenyl-3-(ethylsulfanylcarbonyl)-1,4-(±)-dihydropyridine carboxylate, 5-ethyl 2-methyl-4-ethyl-6-phenyl-3-(2-methoxyethylsulfanylcarbonyl)-1,4-(±)-dihydropyridine-5-carboxylate, 5-ethyl 2-methyl-4-propyl-6-phenyl-3-(ethylsulfanylcarbonyl)-1,4-(±)-dihydropyridine-5-carboxylate, 5-benzyl 2-methyl-4-ethyl-6-phenyl-3-(ethylsulfanylcarbonyl)-1,4-(±)-dihydropyridine-5-carboxylate, 3,5-diethyl 2-methyl-6-phenyl-4-(dimethoxymethyl)-1,4-(±)-dihydropyridine-3,5dicarboxylate, 3,5-diethyl 2-ethyl-6-phenyl-4-methyl-1,4-(±)-dihydropyridine-3,5-dicarboxylate, 5-ethyl 2,4-diethyl-6-phenyl-3-(ethylsulfanylcarbonyl)-1,4-(±)-dihydropyridine-5-carboxylate, and 5-ethyl 2-propyl-4-ethyl-6-phenyl-3-(ethylsulfanylcarbonyl)-1,4-(±)-dihydropyridine-5-carboxylate, or a pharmaceutically acceptable salt thereof.

The dihydropyridines of the present invention can be prepared by methods known to those skilled in the art For example, the Hantzsch condensation involving a 3-amino-2-propenoate ester, an aldehyde, and a β-ketoester. The corresponding pyridines can be prepared by the oxidation of the dihydropyridines using, for example, tetrachloroquinone as the oxidant.

The pyridine derivatives of the present invention are particularly advantageous because they are in an oxidized state compared to the corresponding dihydropyridine derivatives. The oxidation causes (i) the loss of the chiral center and consequently a change in the spatial position of the substituent in 4-position, (ii) the formation of a stable aromatic system; and (iii) a decrease of the pKa value. Some or all these factors can modify affinities and selectivities of the pyridine derivatives in comparison to the dihydropyridine derivatives.

All of the aforesaid compounds of the present invention can be used as is or in the form of a composition, e.g., a pharmaceutical composition, comprising a carrier, e.g., a pharmaceutically acceptable carrier, and an amount, e.g., a therapeutically effective amount, of any of the compounds of formulas (I) and (II).

The present invention further provides a method of treating a mammal comprising selectively blocking one or more of the adenosine receptors of the mammal, particularly the A₃ adenosine receptors, by administering to the mammal at least one compound of formulas (I) and (II).

The pharmaceutically acceptable carriers described herein for example, vehicles, adjuvants, excipients, or diluents, are well-known to those who are skilled in the art and are readily available to the public. It is preferred that the pharmaceutically acceptable carrier be one which is chemically inert to the active compound and one which has no detrimental side effects or toxicity under the conditions of use.

The choice of carrier will be determined in part by the particular active agent, as well as by the particular method used to administer the composition. Accordingly, there is a wide variety of suitable formulations of the pharmaceutical composition of the present invention. The following formulations for oral aerosol, parenteral, subcutaneous, intravenous, intraarterial, intramuscular, interperitoneal, intrathecal, rectal and vaginal administration are merely exemplary and are in no way limiting.

Formulations suitable for oral administration can consist of (a) liquid solutions, such as an effective amount of the compound dissolved in diluents, such as water, saline, or. orange juice; (b) capsules, sachets, tablets, lozenges, and troches, each containing a predetermined amount of the active ingredient, as solids or granules; (c) powders; (d) suspensions in an appropriate liquid; and (e) suitable emulsions. Liquid formulations may include diluents, such as water and alcohols, for example, ethanol benzyl alcohol, and the polyethylene alcohols and polyethylene glycols, either with or without the addition of a pharmaceutically acceptable surfactant, suspending agent, or emulsifying agent. Capsule forms can be of the ordinary hard- or soft-shelled gelatin type containing, for example, surfactants, lubricants, and inert fillers, such as lactose, sucrose, calcium phosphate, and corn starch. Tablet forms can include one or more of lactose, sucrose, mannitol, corn starch, potato starch, alginic acid, microcrystalline cellulose, acacia, gelatin, guar gum, colloidal silicon dioxde, croscarmellose sodium, talc, magnesium stearate, calcium stearate, zinc stearate, stearic acid, and other excipients, colorants, diluents, buffering agents, disintegrating agents, moistening agents, preservatives, flavoring agents, and pharmacologically compatible carriers. Lozenge forms can comprise the active ingredient in a flavor, usually sucrose and acacia or tragacanth, as well as pastilles comprising the active ingredient in an inert base, such as gelatin and glycerin, or sucrose and acacia, emulsions, gels, and the like containing, in addition to the active ingredient, such carriers as are known in the art.

The compounds of the present invention, alone or in combination with other suitable components, can be made into aerosol formulations to be administered via inhalation. These aerosol formulations can be placed into pressurized acceptable propellants, such as dichlorodifluoromethane, propane, nitrogen, and the like. They also may be formulated as pharmaceuticals for non-pressured preparations, such as in a nebulizer or an atomizer.

Formulations suitable for parenteral administration include aqueous and non-aqueous, isotonic sterile injection solutions, which can contain anti-oxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient, and aqueous and non-aqueous sterile suspensions that can include suspending agents, solubilizers, thickening agents, stabilizers, and preservatives. The compound can be administered in a physiologically acceptable diluent in a pharmaceutical carrier, such as a sterile liquid or mixture of liquids, including water, saline, aqueous dextrose and related sugar solutions, an alcohol, such as ethanol, isopropanol, or hexadecyl alcohol, glycols, such as propylene glycol or polyethylene glycol, glycerol ketals, such as 2,2-dimethyl-1,3-dioxolane-4-methanol, ethers, such as poly(ethyleneglycol) 400, an oil, a fatty acid, a fatty acid ester or glyceride, or an acetylated fatty acid glyceride with or without the addition of a pharmaceutically acceptable surfactant, such as a soap or a detergent, suspending agent, such as pectin, carbomers, methylcellulose, hydroxypropylmethylcellulose, or carboxymethylcellulose, or emulsifying agents and other pharmaceutical adjuvants.

Oils, which can be used in parenteral formulations, include petroleum, animal, vegetable, and synthetic oils. Specific examples of oils include peanut, soybean, sesame, cottonseed, corn, olive, petrolatum, and mineral. Suitable fatty acids for use in parenteral formulations include oleic acid, stearic acid, and isostearic acid. Ethyl oleate and isopropyl myristate are examples of suitable fatty acid esters. Suitable soaps for use in parenteral formulations include fatty alkali metal, ammonium, and triethanolamine salts, and suitable detergents include (a) cationic detergents such as, for example, dimethyl dialkyl ammonium halides, and alkyl pyridinium halides, (b) anionic detergents such as, for example, alkyl, aryl, and olefin sulfonates, alkyl, olefin, ether, and monoglyceride sulfates, and sulfosuccinates, (c) nonionic detergents such as, for example, fatty amine oxides, fatty acid alkanolamides, and polyoxyethylenepolypropylene copolymers, (d) amphoteric detergents such as, for example, alkyl-β-aminopropionates, and 2-alkyl-imidazoline quaternary ammonium salts, and (e) mixtures thereof.

The parenteral formulations will typically contain from about 0.5 to about 25% by weight of the active ingredient in solution. Suitable preservatives and buffers can be used in such formulations. In order to minimize or eliminate irritation at the site of injection, such compositions may contain one or more nonionic surfactants having a hydrophile-lipophile balance (HLB) of from about 12 to about 17. The quantity of surfactants in such formulations ranges from about 5 to about 15% by weight. Suitable surfactants include polyethylene sorbitan fatty acid esters, such as sorbitan monooleate and the high molecular weight adducts of ethylene oxide with a hydrophobic base, formed by the condensation of propylene oxide with propylene glycol. The parenteral formulations can be presented in unit-dose or multi-dose sealed containers, such as ampules and vials, and can be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, water, for injections, immediately prior to use. Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules, and tablets of the kind previously described.

The compounds of the present invention may be made into injectable formulations. The requirements for effective pharmaceutical carriers for injectable compositions are well known to those of ordinary skill in the art. See Pharmaceutics and Pharmacy Practice, J. B. Lippincott Co., Philadelphia, Pa., Banker and Chalmers, eds., pages 238-250 (1982), and ASHP Handbook on Injectable Drugs, Toissel, 4th ed., pages 622-630 (1986).

Additionally, the compounds of the present invention may be made into suppositories by mixing with a variety of bases, such as emulsifying bases or water-soluble bases. Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams, or spray formulas containing, in addition to the active ingredient, such carriers as are known in the art to be appropriate.

The compounds of the present invention can be used in the treatment of any disease state or condition involving the release of inositol-1,4,5-triphosphate (IP3), diacylglycerol (DAG), and free radicals and subsequent arachidonic acid cascades Thus, high blood pressure, locomotor hyperactivity, hypertension, acute hypoxia, depression, and infertility can be treated in accordance with the present inventive method, wherein one of the above-described compounds is acutely administered, e.g., within about a few minutes to about an hour of the onset or realization of symptoms. The method also has utility in the treatment of chronic disease states and conditions, in particular those conditions and disease states wherein chronic prophylactic or therapeutic administration of one of the above-described compounds will prevent the onset of symptoms or will reduce recovery time. Examples of disease states and conditions that may be treated in accordance with the present inventive method include inflammatory disorders, such as vascular inflammation and arthritis, allergies, Crohn's disease, asthma, wound healing, stroke, cardiac failure, acute spinal cord injury, acute head injury or trauma, seizure, neonatal hypoxia (cerebral palsy, prophylactic treatment involves chronic exposure through placental circulation), chronic hypoxia due to arteriovenous malformations and occlusive cerebral artery disease, severe neurological disorders related to excitotoxicity, Parkinson's disease, Huntington's chorea, and other diseases of the CNS, cardiac disease, kidney disease, and contraception.

These compounds can be significant cerebral protectants. K. A Jacobson, Trends in Pharmacol. Sci., 19, 182-191 (May 1998). As such, the above compounds can be used to treat and/or protect against a variety of disorders, including, for example, seizures, transient ischemic shock, strokes, focal ischemia originating from thrombus or cerebral hemorrhage, global ischemia originating from cardiac arrest, trauma, neonatal palsy, hypovolemic shock, and hyperglycemia and associated neuropathies. The above method is applicable, for example, where a mammal has or is at risk of having a condition, disorder, or disease state associated with the cellular release of inositol-1,4,5-triphosphate or diacylglycerol. The method is also applicable when a mammal has or is at risk for hyperactivity and the compound in binding to the A₃ adenosine receptors functions as a locomotor depressant.

The present inventive method is also applicable when a mammal has or is at risk for hypertension and the compound in binding to the A₃ adenosine receptors functions as a hypotensive agent. The method is additionally applicable when a mammal has or is at risk for anxiety and the compound in binding to said A₃ adenosine receptors functions as an anxiolytic agent. The method is furthermore applicable when a mammal has or is at risk for cerebral ischemia and the compound in binding to the A₃ adenosine receptors functions as a cerebroprotectant. Moreover, the method is applicable when a mammal has or is at risk for seizures and the compound in binding to the A₃ adenosine receptors functions as an antiseizure agent.

The compounds of the present invention can be administered chronically as well as acutely.

The present inventive method includes the administration to an animal such as a mammal, particularly a human, in need of the desired adenosine receptor-dependent response of an effective amount, e.g., a therapeutically effective amount, of one or more of the aforementioned present inventive compounds or pharmaceutically acceptable salts or derivatives thereof alone or in combination with one or more other pharmaceutically active compounds.

The compounds of the present invention can also be administered as a pharmaceutically acceptable salt known to those skilled in the art. Example of suitable salts include carbonate, bicarbonate, sulfate, bisulfate, nitrate, halides, phosphates, oxalate, acetate, formate, citrates, and amino acid salts.

Some of the compounds of the present invention can be utilized as functionalized congeners for coupling to other molecules, such as amines and peptides. The use of such congeners provide for increased potency, prolonged duration of action, specificity of action, and prodrugs. Water solubility is also enhanced, which allows for reduction, if not complete elimination, of undesirable binding to plasma proteins and partition into lipids. Accordingly, improved pharmacokinetics can be realized.

The present invention further provides a method of characterizing an adenosine receptor, particularly an A₃ receptor, in a substrate comprising contacting the substrate with a compound of the present invention and evaluating the interaction of the compound and the adenosine receptor. The evaluation can provide qualitative information whether a binding has occurred as well as quantitative information as to the extent of binding.

The present invention further provides a method of inhibiting the binding of a ligand or test compound to an adenosine receptor, particularly an A₃ receptor, of a substrate comprising contacting the substrate with a compound of the present invention so that the compound of the present invention binds to the adenosine receptor and inhibits the ligand from binding to the adenosine receptor.

Thus, the compounds of the present invention can be used in vitro as adenosine receptor probes as well as in assays. Thus, for example, the compounds of the present invention may be used to isolate or characterize receptor sites in a cell or tissue. A labeled compound of the present invention can be used to assay the adenosine receptor binding ability of a ligand or test compound. The compounds of the present invention also can be used in vivo for studying their efficacy in the treatment of various diseases or conditions set forth earlier, e.g., those involving the release of IP3. The compounds of the present invention also can be used for angiogenesis.

One skilled in the art will appreciate that suitable methods of administering a compound of the present invention to an animal are available, and, although more than one route can be used to administer a particular compound, a particular route can provide a more immediate and more effective reaction than another route. Accordingly, the above-described methods are merely exemplary and are in no way limiting. The dose administered to an animal, particularly a human, in the context of the present invention should be sufficient to effect a prophylactic or other therapeutic response in the animal over a reasonable time frame. One skilled in the art will recognize that dosage will depend upon a variety of factors including the strength of the particular compound employed, the age, species, condition, and body weight of the animal as well as the severity/stage of the disease or condition. The size of the dose will also be determined by the route, timing and frequency of administration as well as the existence, nature, and extent of any adverse side-effects that might accompany the administration of a particular compound and the desired physiological effect. It will be appreciated by one of skill in the art that various conditions or disease states, in particular chronic conditions or disease states, may require prolonged treatment involving multiple administrations.

Suitable doses and dosage regimens can be determined by conventional range-finding techniques known to those of ordinary skill in the art. Generally, treatment is initiated with smaller dosages, which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under the circumstances is reached. For convenience, the total daily dosage may be divided and administered in portions during the day if desired. In proper doses and with suitable administration of certain compounds, the present invention provides for a wide range of selective adenosine receptor-dependent responses. Exemplary dosages range from about 0.01 to about 100 mg/kg body weight of the animal being treated/day. Preferred dosages range from about 0.1 to about 10 mg/kg body weight/day.

The abbreviations used in this application have the following meaning:

[¹²⁵I]AB-MECA [¹²⁵I]N⁶-(4-amino-3-iodobenzyl)adenosine-5′- N-methyluronamide CGS 21680 2-[4-[(2-carboxyethyl)phenyl]ethylamino]-5′-N- ethylcarbamoyladenosine CHO Chinese hamster ovary HEK cells Human embryonic kidney cells DMF N,N-dimethylformamide DMSO dimethylsulfoxide K_(i) equilibrium inhibition constant R-PIA R-N⁶-phenylisopropyladenosine

The following examples further illustrate the present invention but, of course, should not be construed as in any way limiting its scope.

EXAMPLE 1

This Example illustrates the sources of some of the materials used in the synthesis of dihydropyrdine and pyridine derivatives of the present invention.

Ethyl 3-aminocrotonate (77c), aldehydes (78a-c and 78e), ethyl acetoacetate (79a), ethyl propionylacetate (79b), tetrachloro-1,4benzoquinone (80), acrolein dimethyl acetal (81), ethyl benzoylacetate, 2,2,6-trimethyl-4H-1,3-dioxin-4-one (84), benzyl acetate, N-isopropylcyclohexylamine, all acid chlorides (85, except 85f, obtained by the reaction of the precursor acid with thionyl chloride), 2,2-dimethyl-1,3-dioxane-4,6-dione (86), ethanethiol, propanethiol, and Dowex® 50X8-200 ion exchange resin were purchased from Aldrich (St. Louis, Mo.). 2-Methoxyethanethiol was prepared by a reported method. F. Tisato, et al., J. Med. Chem., 39, 1258-1261 (1996). All other materials were obtained from commercial sources.

EXAMPLE 2

This Example illustrates the various analytical methods employed in the characterization of the compounds of the present invention.

Proton nuclear magnetic resonance spectroscopy was performed on a Varian GEMINI-300 spectrometer, and all spectra were obtained in CDCl₃. Chemical shifts (δ) reported herein are relative to tetramethylsilane. Chemical-ionization (CI) mass spectrometry was performed with a Finnigan 4600 mass spectrometer, and electron-impact (EI) mass spectrometry with a VG7070F mass spectrometer at 6 kV. Elemental analysis was performed by Atlantic Microlab Inc. (Norcross, Ga.). All melting points were determined with a Unimelt capillary melting point apparatus (Arthur H. Thomas Co., PA) and were uncorrected.

EXAMPLE 3

This Example illustrates the general procedure used for the preparation of certain 1,4-dihydropyridine compounds of the present invention. This Example also sets forth the ¹H NMR and the high resolution mass spectral data. of these compounds.

Equimolar amounts (0.5-1.0 mmol) of the appropriate β-enaminoester (77), aldehyde (78), and β-ketoester (79) were dissolved in 2-5 mL of absolute ethanol. The mixture was sealed in a PYREX™ glass tube and heated, with stirring, to 80° C. for 18-24 h. After the mixture cooled to room temperature, the solvent was evaporated and the residue was purified by preparative TLC (silica 60; 1000 or 2000 mm; Analtech, Newark, DE; petroleum ether-ethyl acetate (4:1-9:1)). The products were shown to be homogeneous by analytical TLC and were stored at −20° C.

The ¹H NMR and the high resolution mass spectral data of these compounds are set forth below:

3-Propyl 5-ethyl 2,4-dimethyl-6-phenyl-1,4-(±)-dihydropyridine-3,5-dicarboxylate (60)

¹NMR d: 0.91 (t, J=6.9 Hz, 3 H),1.00 (t, J=6.9 Hz, 3 H), 1.13 (d, J=6.9 Hz, 3 H), 1.72 (m, 2 H), 2.30 (s, 3 H), 3.88-4.00 (m, 3 H), 4.15 (m, 2 H), 5.69 (s, br, 1 H), 7.28-7.31 (m, 2 H), 7.39-7.42 (m, 3 H). MS (CI/NH₃): m/z 361 (M⁺+NH₄), 344 (M⁺+1). MS (EI): m/z 343 (M⁺), 328 (M⁺−CH₃, base), 314 (M⁺−CH₂CH₃), 284 (M⁺−OPr).

3,5-Diethyl 2-methyl-4-ethyl-6-phenyl-1,4-(±)-dihydropyridine-3,5-dicarboxylate (61)

¹H NMR d: 0.87-0.92 (m, 6 H), 1.31 (t, J=6.9 Hz, 3 H), 1.52 (m, 2 H), 2.32 (s, 3 H), 3.90 (m, 2 H), 4.03. (t, J=5.9 Hz, 1 H), 4.20 (m, 2 H), 5. 71 (s, br, 1 H), 7.30-7.40 (m, 5 H). MS (CI/NH₃): m/z 361 (M⁺+NH₄, base), 344 (M⁺+1), 3:14 (M⁺−C₂H₅). MS (EI): m/z 314 (M^(+−CH) ₂CH₃, base), 298 (M⁺−OCH₂CH₃).

5-Ethel 2-methyl-4ethyl-6-phenyl-3-(ethylsulfanylcarbonyl)-1,4-(±)-dihydropyridine-5-carboxylate (62)

¹H NMR d: 0.90-0.96 (m, 6 H), 1.29 (t, J=7.8 Hz, 3 H), 1.57 (m, 2 H), 2.33 (s, 3 H), 2.93 (q, J=7.8 Hz, 2 H), 3.94 (q, J=6.9 Hz, 2 H), 4.03 (t, J=4.8 Hz, 1 H), 4.19 (q, J=6.0 Hz, 2 H), 5. 81 (s, br, 1 H), 7.30-7.32 (m, 2 H), 7.40-7.42 (m, 3 H). MS (CI/NH₃): m/z 377 (M⁺+NH₄, base), 314 (M⁺−OEt), 298 (M⁺−SEt). MS (EI): m/z 330 (M⁺−CH₂CH₃, base), 314 (M⁺−OEt), 298 (M⁺−SEt), 286 (M⁺−CO₂Et).

5-Ethyl 2-methyl-4-ethyl-6-phenyl-3-[(2-methoxy-(ethylsulfanylcarbonyl)]-1,4-(±)-dihydropyridine-5-carboxylate (63)

¹H NMR d: 0.91 (t, J=7.8 Hz, 3H), 0.92 (t, J=7.8 Hz, 3 H), 1.60 (m, 2 H), 2.32 (s, 3 H), 3.14 (t, J=6.9 Hz, 2 H), 3.38 (s, 3 H), 3.55 (t, J=6.9 Hz, 2 H), 3.93 (q, J=7.8 Hz, 2 H), 4.20 (t, J=6.0 Hz, 1 H), 5.91 (s, br, 1 H), 7.28-7.32 (m, 2 H), 7.38-7.42 (m, 3 H). MS (CI/NH₃): m/z 405 (M⁺+NH₄, base), 387 (M⁺).

5-Ethyl 2-methyl-4-propyl-6-phenyl-3-(ethylsulfanylcarbonyl)-1,4-(±)-dihydropyridine-5-carboxylate (64)

¹NMR d: 0.90 (t, J=7.8 Hz, 3 H), 0.92 (t, J=7.8 Hz, 3 H), 1.29 (t, J=7.8 Hz, 3 H), 1.39 (m, 2 H), 1.49 (m, 2 H), 2.32 (s, 3 H), 2.92 (q, J=7.8 Hz, 2 H), 3.92 (q, J=7.8 Hz, 2 H), 4.19 (t, J=6.0Hz, 1 H), 5.98 (s, br, 1 H), 7.27-7.31 (m, 2 H), 7.38-7.41 (m, 3 H). MS (CI/NH₃): m/z 391 (M⁺+NH₄, base), 373 (M⁺). MS (EI): m/z 330 (M⁺−CH₂CH₂CH₃, base), 314 (MH⁺−OEt—Me), 284 (M⁺−COSEt).

5-Benzyl 2-methyl-4ethyl-6-phenyl-3-(ethylsulfanylcarbonyl)-1,4-(±)-dihydropyridine-5-carboxylate (65)

¹H NMR d: 0.92 (t, J=7.8 Hz, 3 H), 1.29 (t, J=7.8 Hz, 3 H), 1.55-1.64 (m, 2 H), 2.32 (s, 3 H), 2.92 (q, J=7.8 Hz, 2 H), 4.24 (t, J=6.0 Hz, 1 H), 4.96 (AB, J=12.6 Hz, 2 H), 5.86 (s, br, 1 H), 6.98-7.00 (m, 1 H), 7.22-7.40 (m, 9 H). MS (CI/NH₃): m/z 439 (M⁺+NH₄, base), 421 (M⁺), 360 (M⁺−SEt).

3,5-Diethyl 2-methyl-6-phenyl-4-(dimethoxymethyl)-1,4-(±)-dihydropyridine-3,5-dicarboxylate (66)

¹H NMR d:0.91(t, J=6.9 Hz, 3 H), 1.33 (t,J=6.9 Hz, 3 H), 2.33 (s, 3 H), 3.38 (s, 3 H), 3.39 (s, 3 H), 3.93 (q, J=6.9 Hz, 2 H), 4.14 (d, J=6.0 Hz, 1 H), 4.22 (q, J=6.9 Hz, 2 H), 4.48 (d, J=6.0 Hz, 2 H), 5.84 (s, br, 1 H), 7.31-7.35 (m, 2 H), 7.38-7.40 (m, 3 H). MS (CI/NH₃): m/z 407 (M⁺+NH₄), 390 (M⁺+1), 358 (M⁺−OMe, base).

3-Ethyl 5-benzyl 2-methyl-4-phenylethynyl-6-cyclopropyl-1,4-(±)-dihydropyridine-3,5-dicarboxylate (70)

¹H NMR: δ0.59 (m, 1 H), 0.88-1.03 (m, 2 H), 1.18-1.28 (m, 1 H), 1.32 (t, J=7.8 Hz, 3 H), 2.31 (s, 3 H), 2.73-2.83 (m, 1 H), 4.17-4.35 (m, 2 H), 5.09 (s, 1 H), 5.29 (AB, J=12.9 Hz, 2H), 5.56 (s, br, 1 H), 7.22-7.47 (m, 10 H). MS (EI): m/z 441 ), 412 (M⁺−CH₂CH₃,), 368 (M⁺−CO₂Et), 350 (M⁺−CH₂Ph), 306 (M⁺−CO₂CH₂Ph), 91 (CH₂Ph, base).

3-Ethyl 5-benzyl 2-methyl-4-phenylethynyl-6-cyclobutyl-1,4-(±)-dihydropyridine-3,5-dicarboxylate (71)

¹H NMR: δ1.32 (t, J=6.9 Hz, 3 H), 1.79-2.29 (m, 6 H), 2.37-2.40 (m, 1 H), 2.38 (s, 3 H), 4.21-4.27 (m, 2 H), 5.07 (s, 1 H), 5.26 (AB, J=12.6 Hz, 2 H), 6.10 (s, br, 1 H), 7.21-7.46 (m, 10 H). MS (EI): m/z 455 (M⁺), 426 (M⁺−CH₂CH₃,), 382 (M⁺−CO₂Et), 364 (M⁺−CH₂Ph), 320 (M⁺−CO₂CH₂Ph), 91 (⁺CH₂Ph, base).

3-Ethyl 5-benzyl 2-methyl-4-phenylethynyl-6-cyclopentyl-1,4(±)-dihydropyridine-3,5-dicarboxylate (72)

¹H NMR: δ1.23-1.37 (m, 4 H), 1.32 (t, J=6.9 Hz, 3 H), 1.70 (m, 4 H), 2.00 (m, 1 H), 2.35 (s, 3 H), 4.24 (m, 2 H), 5.09 (s, 1 H), 5.27 (AB, J=12.9 Hz, 2 H), 5.90 (s, br, 1 H), 7.22-7.46 (m, 10 H). MS (EI): m/z 487 (M⁺+NH₄), 470 (M⁺+1).

3-Ethyl 5-benzyl 2-methyl-4-phenylethynyl-6-cyclohexyl-1,4-(±)-dihydropyridine-3,5-dicarboxylate (73)

¹H NMR: δ1.13-1.38 (m, 6 H), 1.32 (t, J=6.9 Hz, 3 H), 1.65-1.89 (m, 5 H),2.35 (s, 3 H), 4.22 (q, J=6.9 Hz, 2 H), 5.09 (s, 1 H), 5.27 (AB, J=12.6 Hz, 2 H), 5.99 (s, br, 1 H), 7.21-7.46 (m, 10 H). MS (EI): m/z 483 (M⁺), 454 (M⁺−CH₂CH₃,), 400 (M⁺−C₆H₁₁), 410 (M⁺−CO₂Et), 392 (M⁺−CH₂Ph), 348 (M⁺−CO₂CH₂Ph), 91 (⁺CH₂Ph, base).

3,5-Diethyl 2-ethyl-6-phenyl-4-methyl-1,4-(±)-dihydropyridine-3,5-dicarboxylate (74)

¹H NMR d: 0.90 (t, J=6.9 Hz, 3 H), 1.12 (d, J=6.9 Hz, 3 H), 1.19 (t, J=6.9 Hz, 3 H), 1.32 (t, J=6.9 Hz, 3 H), 2.50 (m, 1 H ), 2.90 (m, 1 H), 3.89-3.98 (m, 3 H), 4.22 (m, 2 H), 5.73 (s, br, 1 H), 7.30-7.31 (m, 2 H), 7.40-7.42 (m, 3 H). MS (CI/NH₃): m/z 361 (M⁺+NH₄), 344 (M⁺+1). MS (EI): m/z 343 (M⁺), 328 (M⁺−CH_(3,) base), 298 (M⁺−OEt).

5-Ethyl 2,4-diethyl-6-phenyl-3-(ethylsulfanylcarbonyl)-1,4-(±)-dihydropyridine-5-carboxylate (75)

¹H NMR d: 0.89 (m, 6 H), 0.93 (t, J=6.9 Hz, 3 H), 1.19 (t, J=7.8 Hz, 3 H), 1.58 (m, 2 H), 2.69 (m, 2 H), 2.92 (q, J=7.8 Hz, 2 H), 3.92 (q, J=6.9 Hz, 2 H , 4.02 (t, J=6.0 Hz, 1 H), 5.94 (s, br, 1 H), 7.32 (m, 2 H), 7.41 (m, 3 H). MS (CI/NH₃): m/z 391 (M⁺+NH₄ base), 374 (M⁺+1), 312 (M⁺−SEt). MS (EI): m/z 373 (M⁺), 344 (M⁺−CH₂CH₃), 328 (M⁺−OEt, base), 312 (M⁺−SEt).

5-Ethyl 2-propyl-4-ethyl-6-phenyl-3-(ethylsulfanylcarbonyl)-1,4-(±)-dihydropyridine-5-carboxylate (76)

¹H NMR d: 0.90-0.96 (m, 6 H), 0.99 (t, J=7.8 Hz, 3 H), 1.29 (t J=7.8 Hz, 3 H), 1.53-1.66 (m, 4 H), 2.66 (m, 2 H), 2.92 (q, J=6.9 H 2 H), 3.95 (q, J=7.8 Hz, 2 H), 4.20 (t, J=6.0 Hz, 1 H), 5.85 (s, br, 1 H), 7.30-7.32 (m, 2 H), 7.41-7.43 (m, 3 H). MS (CI/NH₃): m/z 405 (MS⁺+NH₄), 388 (M⁺+1), 326 (M⁺−SEt).

EXAMPLE 4

This Example illustrates a preparation of an aldehyde group containing dihydropyridine. The reaction involved is illustrated in FIG. 3.

Dihydropyridine 66 (14 mg) and a catalytic amount of Dowex® 50X8-200 resin were stirred in a mixture of acetone (2 mL) and water (0.5 mL) at room temperature for 48 h. The resin was filtered off, and the filtrate was dried with anhydrous MgSO₄. The solvent was removed, and the residue was purified with preparative TLC (silica 60; 1000 mm; Analtech, Newark, DE; petroleum ether-ethyl acetate (3:1)) to give 10 mg of the desired product.

3,5-Diethyl 2-methyl-6-phenyl-4-formyl-1,4(±)-dihydropyridine-3,5-dicarboxylate (67), yield: 82%. The ¹HNMR and high resolution mass spectral data of 67 are set forth below.

¹H NMR d: 0.89 (t, J=6.9 Hz, 3 H), 1.32 (t, J=6.9 Hz, 3 H), 2.37 (s, 3 H), 3.94 (q, J=6.9 Hz, 2 H), 4.24 (d, J=6.9 Hz, 2 H), 4.90 (s, 1 H), 5.81 (s, br, 1 H), 7.35 (m, 2 H), 7.41 (m, 3 H), 9.66 (s, 1 H). MS (CI/NH₃): m/z 361 (M⁺+NH₄), 344 (M⁺+1), 314 (M⁺−CHO, base). MS (EI): m/z 343 (M⁺−), 314 (M⁺−CHO, base), 298 (M⁺−OEt). HRMS: Calcd. for C₁₈H₂₀NO₄ (M⁺−CHO) 314.1392; found, 314.1432.

EXAMPLE 5

This Example illustrates a procedure for the oxidation of the 1,4-dihydropyridines into the corresponding pyridine derivatives. The reaction is schematically shown in FIG. 4.

Equimolar amounts of the 1,4-dihydropyrdines (60-67, 70-76, 81a-i, ˜0.2 mmol) and tetrachloro-1,4-benzoquinone (80) in THF (2-4 mL) were mixed and refluxed overnight. After the mixture cooled to room temperature, the solvent was removed, and the residue was purified by preparative TLC (silica 60; 1000 mm; Analtech, Newark, Del.; petroleum ether-ethyl acetate (9:1-19:1)) to give the desired products. The ¹H NMR and high resolution mass spectral data of some of the pyridine compounds of the present invention are set forth below.

3-Propyl 5-ethyl 2,4-dimethyl-6-phenylpyridine-3,5-dicarboxylate (34)

¹H NMR d: 0.97-1.06 (m, 6 H), 1.81 (m, 2 H), 2.37 (s, 3 H), 2.61 (s, 3 H), 4.11 (t, J=6.9 Hz, 2 H), 4.35 (t, J=6.9 Hz, 2 H), 7.40-7.43 (m, 3 H), 7.56-7.57 (m, 2 H). MS (EI): m/z 341 (M⁺), 312 (M⁺−CH₂CH₃, base), 296 (M⁺−OCH₂CH₃), 282 (M⁺−OPr). HRMS: calcd for C₂₀H₂₃NO₄ 341.1627, found 341.1635.

3,5-Diethyl 2-methyl-4-ethyl-6-phenylpyridine-3,5-dicarboxylate (35)

¹H NMR d: 0.97 (t, J=6.9 Hz, 3 H), 1.24 (t, J=7.8 Hz, 2 H), 1.43 (t, J=6.9 Hz, 3 H), 2.61 (s, 3 H), 2.71 (q, J=7.8 Hz, 2 H), 4.09 (q, J=6.9 Hz, 2 H), 4.46 (q, J=6.9 Hz, 2 H), 7.40-7.43 (m,3 H), 7.55-7.58 (m, 2 H). MS (EI): m/z 341 (M⁺), 312 (M⁺−CH₂CH₃, base), 296 (M⁺−OCH₂CH₃), 284 (MH⁺−2xEt), 268 (M⁺−CO₂Et), 240 (MH⁺−Et—CO₂Et). HRMS: calcd. for C₂₀H₂₃NO₄ 341.1627, found 341.1615.

5-Ethyl 2-methyl-4-ethyl-3-(ethylsulfanylcarbonyl)-6-phenylpyridine-5-carboxylate (36)

¹H NMR d: 0.97 (t, J=6.9 Hz, 3 H), 1.23 (t, J=7.8 Hz, 3 H), 1.41 (t, J=7.8 Hz, 3 H), 2.61 (s, 3 H), 2.74 (q, J=7.8 Hz, 2 H), 3.14 (q, J=7.8 Hz, 2 H), 4.09 (q, J=6.9 Hz, 2 H), 7.40-7.44 (m, 3 H), 7.56-7.59 (m, 2 H). MS (CI/NH₃): m/z 375 (M⁺+NH₄), 358 (M⁺+1, base). MS (EI): m/z 357 (M⁺), 312 (M⁺−OEt), 296 (M⁺−SEt, base), 268 (M⁺−COSEt).

5-Ethyl 2-methyl-4-ethyl-3-[2-methoxy-(ethylsulfanylcarbonyl)]-6-phenylpyridine-5-carboxylate (37)

¹H NMR d: 0.97 (t, J=7.8 Hz, 3 H), 1.23 (t, J=7.8 Hz, 3 H), 2.62 (s, 3 H), 2.74 (q, J=7.8 Hz, 2 H), 3.36 (t, J=6.0 Hz, 2 H), 3.42 (s, 3 H), 3.67 (t, J=6.0 Hz, 2 H), 4.09 (q, J=7.8 Hz, 2 H), 7.39-7.42 (m, 3 H), 7.55-7.58 (m, 2 H). MS (CI/NH₃): m/z 388 (M⁺+1), 296 (M⁺−CH₃OCH₂CH₂S).

5-Ethyl-2-methyl-4-propyl-3-(ethylsulfanylcarbonyl)-6-phenylpyridine-5-carboxylate (38)

¹H NMR d: 0.95 (t, J=6.9 Hz, 3 H), 0.97 (t, J=6.9 Hz, 3 H), 1.41 (t, J=7.8 Hz, 3 H), 1.63 (m, 2 H), 2.61 (s, 3 H), 2.68 (t, J=7.8 Hz, 2 H), 3.14 (q, J=6.9 Hz, 2 H), 4.08 (q, J=6.9 Hz, 2 H), 7.41 (m, 3 H), 7.56 (m, 2 H). MS (CI/NH₃): m/z 372 (M⁺+1). MS (EI): m/z 326 (M⁺−OCH₂CH₃), 310 (M⁺−SEt, base), 282 (M⁺−COSEt).

5-Benzyl 2-methyl-4-ethyl-3-(ethylsulfanylcarbonyl)-6-phenylpyridine-5-carboxylate (39)

¹H NMR d: 1.18 (t, J=7.8 Hz, 3 H), 1.40 (t, J=7.8 Hz, 3 H), 2.60 (s, 3 H), 2.70 (q, J=7.8 Hz, 2 H), 3.12 (q, J=7.8 Hz, 2 H), 5.04 (s, 2 H), 6.96-6.98 (m, 2 H), 7.22-7.28 (m, 3 H), 7.38-7.40 (m, 3 H), 7.55-7.58 (m, 2 H). MS (CI/NH₃): m/z 420 (M⁺1, base).

3,5-Diethyl 2-methyl-4-(dimethoxymethyl)-6-phenylpyridine-3,5-dicarboxylate (40)

¹H NMR d: 1.00 (t, J=6.9 Hz, 3 H), 1.41 (t, J=6.9 Hz, 3 H), 2.62 (s, 3 H), 3.33 (s, 6 H), 4.07 (q, J=6.9 Hz, 2 H), 4.41 (d, J=6.9 Hz, 2 H), 5.76 (s, 1 H), 7.40-7.42 (m, 3 H), 7.53-7.55 (m, 2 H). MS (CI/NH₃): m/z 388 (M⁺+1). HRMS: calcd for C₂₁H₂₅NO₆ 387.1682, found 387.1674.

3,5-Diethyl 2-methyl-4-formyl-6-phenylpyridine-3,5-dicarboxylate (41)

¹H NMR d: 1.06 (t, J=7.8 Hz, 3 H), 1.43 (t, J=6.9 Hz, 3 H), 2.94 (s, 3 H), 4.17 (q, J=7.8 Hz, 2 H), 4.42 (d, J=6.9 Hz, 2 H), 7.43-7.45 (m, 3 H), 7.55 (m, 2 H), 8.63 (s, 1 H). MS (CI/NH₃): m/z 342 (M⁺+1).

3-Ethyl 5-benzyl 2-methyl-4-phenylethynyl-6-cyclobutylpyridine-3,5-dicarboxylate (44)

¹H NMR: δ1.37 (t, J=7.8 Hz, 3 H), 1.81-1.98 (m, 2 H), 2.11-2.19 (m, 2 H), 2.37-2.47 (m, 2 H), 2.61 (s, 3 H), 3.70 (m, 1 H), 4.43 (q, J=7.8 Hz, 2 H), 5.39 (s, 2 H), 7.28-7.40 (m, 10 H). MS (EI): m/z 454 (M⁺+1).

3-Ethyl 5-benzyl 2-methyl-4-phenylethynyl-6-cyclopentylpyridine-3,5-dicarboxylate (45)

¹H NMR: δ1.37 (t, J=7.8 Hz, 3 H), 1.54-1.58 (m, 2 H), 1.78-1.88 (m, 6 H) 2.57 (s, 3 H), 3.04 (m, 1 H), 4.43 (q, J=7.8 Hz, 2 H), 5.41 (s, 2 H), 7.29-7.44 (m, 10 H). MS (EI): m/z 467 (M⁺), 376 (M⁺−CH₂Ph), 91 (⁺CH₂Ph, base).

3,5-Diethyl 2-ethyl-4-methyl-6-phenylpyridine-3,5-dicarboxylate (46)

¹H NMR d: 1.00 (t, J=6.9 Hz, 3 H), 1.33 (t, J=7.8 Hz, 3 H), 1.42 (t, J=6.9 Hz, 3 H), 2.36 (s, 3 H), 2.86 (q, J=7.8 Hz, 2 H), 4.12 (q, J=6.9 Hz, 2 H), 4.45 (q, J=6.9 Hz, 2 H), 7.40-7.43 (m, 3 H), 7.58-7.60 (m, 2 H). MS (EI): m/z 341 (M⁺), 312 (M⁺−CH₂CH₃, base), 296 (M⁺−OEt), 284 (MH⁺−2xEt), 269 (MH⁺−CO₂Et). HRMS: calcd for C₂₀H₂₃NO₄ 341.1627, found 341.1631.

2-Methyl-4-ethyl-5-ethoxycarbonyl-6-phenylpyridine-3-carboxylic acid (47)

¹H NMR d: 0.97 (t, J=7.8 Hz, 3 H), 1.24 (t, J=7.8 Hz, 3 H), 2.61 (s, 3 H), 2.71 (q, J=7.8 Hz, 2 H), 4.46 (J=7.8 Hz, 2 H), 7.40-7.45 (m, 3 H), 7.55-7.59 (m, 2 H). MS (CI/NH₃): m/z 314 (M⁺1). MS (EI): m/z 312 (M⁺−1), 296 (M⁺−OH), 284 (M⁺−Et, base).

5-Ethyl 2,4-diethyl-3-(ethylsulfanylcarbonyl)-6-phenylpyridine-5-carboxylate (48)

¹H NMR d: 0.98 (t, J=7.8 Hz, 3 H), 1.23 (t, J=7.8 Hz, 3 H), 1.34 (t, J=6.9 Hz, 3 H), 1.41 (t, J=7.8 Hz, 3 H), 2.73 (q, J=7.8 Hz, 2 H), 2.87 (q, J=7.8 Hz, 2 H), 3.14 (q, J=7.8 Hz, 2 H), 4.10 (q, J=6.9 Hz, 2 H), 7.41-7.44 (m, 3 H), 7.58-7.61 (m, 2 H). MS (CI/NH₃): m/z 372 (M⁺+1, base).

5-Propyl 2,4-diethyl-3-(ethylsulfanylcarbonyl)-6-phenylpyridine-5-carboxylate (49a)

¹H NMR d: 0.65 (t, J=7.8 Hz, 3 H), 1.23 (t, J=7.8 Hz, 3 H), 1.34 (t, J=7.8 Hz, 3 H), 1.41 (t, J=7.8 Hz, 3 H), 1.34-1.44 (m, 2 H), 2.73 (q, J=7.8 Hz, 2 H), 2.87 (q, J=7.8 Hz, 2 H), 3.14 (q, J=7.8 Hz, 2 H), 3.99 (t, J=6.9 Hz, 2 H), 7.40-7.44 (m, 3 H), 7.59-7.62 (m, 2 H). MS (CI/NH₃): m/z 404 (MH⁺+NH₄), 386 (M⁺+1, base).

5-Propyl 2-ethyl-4-propyl-3-(ethylsulfanylcarbonyl)-6-phenylpyridine-5-carboxylate (49b)

¹H NMR d: 0.66 (t, J=7.8 Hz, 3 H), 0.95 (t, J=7.8 Hz, 3 H), 1.34 (t, J=7.8 Hz, 3 H), 1.41 (t, J=7.8 Hz, 3 H), 1.40 (m, 2 H), 1.63 (m, 2 H), 2.66 (t, J=7.8 Hz, 2 H), 2.86 (q, J=7.8 Hz, 2 H), 3.13 (q, J=7.8 Hz, 2 H), 3.98 (t, J=6.9 Hz, 2 H), 7.39-7.44 (m, 3 H), 7.58-7.62 (m, 2 H). MS (CI/NH₃): m/z 400 (M⁺+1, base).

5-Hydroxylethyl 2,4-diethyl-3-(ethylsulfanylcarbonyl)-6-phenylpyridine-5-carboxylate (40)

¹H NMR d: 1.24 (t, J=7.8 Hz, 3 H), 1.34 (t, J=7.8 Hz, 3 H), 1.42 (t, J=7.8 Hz, 3 H), 2.75 (q, J=7.8 Hz, 2 H), 2.87 (q, J=7.8 Hz, 2 H), 3.15 (q, J=7.8 Hz, 2 H), 3.48 (m, 2 H), 4.13 (t, J=4.8 Hz, 2 H), 7.45-7.49 (m, 3 H), 7.60-7.63 (m, 2 H). MS (CI/NH₃): m/z 404 (M⁺+NH₄−1), 388 (M⁺+1).

5-Ethyl 2,4-diethyl-3-(ethylsulfanylcarbonyl)-6-(m-chlorophenyl)pyridine-5-carboxylate (51)

¹H NMR d: 1.07 (t, J=7.8 Hz, 3 H), 1.23 (t, J=7.8 Hz, 3 H), 1.34 (t, J=7.8 Hz, 3 H), 1.41 (t, J=7.8 Hz, 3 H), 2.72 (q, J=7.8 Hz, 2 H), 2.86 (q, J=7.8 Hz, 2 H), 3.14 (q, J=7.8 Hz, 2 H), 4.16 (q, J=7.8 Hz, 2 H), 7.35-7.41 (m, 1 H), 7.46-7.50 (m, 1 H), 7.62 (s, 1 H). MS (CI/NH₃): m/z 406 (M⁺+1).

5-Ethyl 2,4-diethyl-3-(ethylsulfanylcarbonyl)-6-cyclopentylpyridine-5-carboxylate (52)

¹H NMR d: 1.18 (t, J=7.8 Hz, 3 H), 1.27 (t, J=7.8 Hz, 3 H), 1.38 (t, J=7.8 Hz, 3 H), 1.39 (t, J=7.8 Hz, 3 H), 1.63 (m, 2 H), 1.92 (m, 7 H), 2.58 (q, J=7.8 Hz, 2 H), 2.76 (q, J=7.8 Hz, 2 H), 3.91 (q, J=7.8 Hz, 2 H), 4.40(q, J=7.8 Hz, 2 H). HRMS: calcd for C₂₀H₂₉NO₃S 363.1868, found 363.1858.

5-Ethyl 2,4-diethyl-3-propylsulfanylcarbonyl-6-phenylpyridine-5-carboxylate (53)

¹H NMR d: 0.98 (t, J=7.8 Hz, 3 H), 1.07 (t, J=7.8 Hz, 3 H), 1.23 (t, J=7.8 Hz, 3 H), 1.34 (t, J=7.8 Hz, 3 H), 1.76 (m, 2 H), 2.73 (q, J=7.8 Hz, 2 H), 2.87 (q, J=7.8 Hz, 2 H), 3.12 (q, J=7.8 Hz, 2 H), 4.10 (q, J=7.8 Hz, 2 H), 7.42-7.43 (m, 3 H), 7.58-7.61 (m, 2 H). MS (CI/N₃): m/z 386 (M⁺+1, base).

5-Propyl 2,4-diethyl-3-propylsulfanylcarbonyl-6-(m-chlorophenyl)pyridine-5-carboxylate (54)

¹H NMR d: 0.72 (t, J=7.8 Hz, 3 H), 1.07 (t, J=7.8 Hz, 3 H), 1.23 (t, J=7.8 Hz, 3 H), 1.34 (t, J=7.8 Hz, 3 H), 1.46 (m, 2 H), 1.77 (m, 2 H), 2.72 (q, J=7.8 Hz, 2 H), 2.86 (q, J=7.8 Hz, 2 H), 3.13 (t, J=6.9 Hz, 2 H), 4.04 (t, J=6.9 Hz, 2 H), 7.37 (m, 2 H), 7.48 (m, 1 H), 7.62 (s, 1 H). MS (CI/NH₃): m/z 434 (M⁺(C₂₃H₂₈ ³⁵ClNO₃S)+1, base), 404 (M⁺−C₂ H₅), 358 (M⁺−PrS).

5-Ethyl 2-propyl-4-ethyl-3-(ethylsulfanylcarbonyl)-6-phenylpyridine-5-carboxylate (55)

¹H NMR d: 0.99 (t, J=6.9 Hz, 6 H), 1.23 (t, J=7.8 Hz, 3 H), 1.41 (t, J=7.8 Hz, 3 H), 1.82 (m, 2 H), 2.72 (q, J=6.9 Hz, 2 H), 2.81 (q, J=6.9 Hz, 2 H), 3.14 (q, J=7.8 Hz, 2 H), 4.10 (q, J=7.8 Hz, 2 H), 7.40-7.44 (m, 3 H), 7.57-7.60 (m, 2 H). MS (EI): m/z 385 (M⁺), 340 (M⁺−OEt), 324 (M⁺−SEt), 296 (M⁺−COSEt).

5-Ethyl 2-(2-methoxylethyl)-4-ethyl-3-(ethylsulfanylcarbonyl)-6-phenylpyridine-5-carboxylate (56)

¹H NMR d: 0.99 (t, J=7.8 Hz, 3 H), 1.23 (t, J=7.8 Hz, 3 H), 1.41 (t, J=7.8 Hz, 3 H), 2.73 (q, J=7.8 Hz, 2 H), 3.11-3.18 (m, 4 H), 3.37 (s, 3 H), 3.85 (t, J=7.8 Hz, 2 H), 4.10 (q, J=7.8 Hz, 2 H), 7.42-7.44 (m, 3 H), 7.58-7.61 (m, 2 H). MS (CI/NH₃): m/z 402 (MH⁺, base). HRMS: calcd. for C₂₂H₂₇NO₄S 401.1661, found 401.1666.

5-Ethyl 2-butyl-4-ethyl-3-(ethylsulfanylcarbonyl)-6-phenylpyridine-5-carboxylate (49a)

¹H NMR d: 0.65 (t, J=7.8 Hz, 3 H), 1.23 (t, J=7.8 Hz, 3 H), 1.34 (t, J=7.8 Hz, 3 H), 1.41 (t, J=7.8 Hz, 3 H), 1.34-1.44 (m, 2 H), 2.73 (q, J=7.8 Hz, 2 H), 2.87 (q, J=7.8 Hz, 2 H), 3.14 (q, J=7.8 Hz, 2 H), 3.99 (t, J=6.9 Hz, 2 H), 7.40-7.44 (m, 3 H), 7.59-7.62 (m, 2 H). MS (CI/NH₃): m/z 404 (MH⁺+NH₄), 386 (M⁺+1, base).

5-Propyl 2-ethyl-4-propyl-3-(ethylsulfanylcarbonyl)-6-phenylpyridine-5-carboxylate (49b)

¹H NMR d: 0.66 (t, J=7.8 Hz, 3 H), 0.95 (t, J=7.8 Hz, 3 ), 1.34 (t, J=7.8 Hz, 3 H), 1.41 (t, J=7.8 Hz, 3 H), 1.40 (m, 2 H), 1.63 (m, 2 H), 2.66 (t, J=7.8 Hz, 2 H), 2.86 (q, J=7.8 Hz, 2 H), 3.13 (q, J=7.8 Hz, 2 H), 3.98 (t, J=6.9 Hz, 2 H), 7.39-7.44 (m, 3 H), 7.58-7.62 (m, 2 H). MS (CI/NH₃): m/z 400 (M⁺+1, base).

5-Hydroxylethyl 2,4-diethyl-3-(ethylsulfanylcarbonyl)-6-phenylpyridine-5-carboxylate (40)

¹H NMR d: 1.24 (t, J=7.8 Hz, 3 H), 1.34 (t, J=7.8 Hz, 3 H), 1.42 (t, J=7.8 Hz, 3 H), 2.75 (q, J=7.8 Hz, 2 H), 2.87 (q, J=7.8 Hz, 2 H), 3.15 (q, J=7.8 Hz, 2 H), 3.48 (m, 2 H), 4.13 (t, J=4.8 Hz, 2 H), 7.45-7.49 (m, 3 H), 7.60-7.63 (m, 2 H). MS (CI/NH₃): m/z 404 (M⁺+NH₄−1), 388 (M⁺1).

5-Ethyl 2,4-diethyl-3-(ethylsulfanylcarbonyl)-6-(m-chlorophenyl)pyridine-5-carboxylate (51)

¹H NMR d: 1.07 (t, J=7.8 Hz, 3 H), 1.23 (t, J=7.8 Hz, 3 H), 1.34 (t, J=7.8 Hz, 3 H), 1.41 (t, J=7.8 Hz, 3 H), 2.72 (q, J=7.8 Hz, 2 H), 2.86 (q, J=7.8 Hz, 2 H), 3.14 (q, J=7.8 Hz, 2 H), 4.16 (q, J=7.8 Hz, 2 H), 7.35-7.41 (m, 1 H), 7.46-7.50 (m, 1 H), 7.62 (s, 1 H). MS (CI/NH₃): m/z 406 (M⁺+1).

5-Ethyl 2,4-diethyl-3-(ethylsulfanylcarbonyl)-6-cyclopentylpyridine-5-carboxylate (52)

¹H NMR d: 1.18 (t, J=7.8 Hz, 3 H), 1.27 (t, J=7.8 Hz, 3 H), 1.38 (t, J=7.8 Hz, 3 H), 1.39 (t, J=7.8 Hz, 3 H), 1.63 (m, 2 H), 1.92 (m, 7 H), 2.58 (q, J=7.8 Hz, 2 H), 2.76 (q, J=7.8 Hz, 2 H), 3.91 (q, J=7.8 Hz, 2 H), 4.40 (q, J=7.8 Hz, 2 H). HRMS: calcd for C₂₀H₂₉NO₃S 363.1868, found 363.1858.

5-Ethyl 2,4-diethyl-3-(propylsulfanylcarbonyl)-6-phenylpyridine-5-carboxylate (53)

¹H NMR d: 0.98 (t, J=7.8 Hz, 3 H), 1.07 (t, J=7.8 Hz, 3 H), 1.23 (t, J=7.8 Hz, 3 H), 1.34 (t, J=7.8 Hz, 3 H), 1.76 (m, 2 H), 2.73 (q, J=7.8 Hz, 2 H), 2.87 (q, J=7.8 Hz, 2 H), 3.12 (q, J=7.8 Hz, 2 H), 4.10 (q, J=7.8 Hz, 2 H), 7.42-7.43 (m, 3 H), 7.58-7.61 (m, 2 H). MS (CI/NH₃): m/z 386 (M⁺+1, base).

5-Propyl 2,4-diethyl-3-(propylsulfanylcarbonyl)-6-(m-chlorophenyl)pyridine-5-carboxylate (54)

¹H NMR d: 0.72 (t, J=7.8 Hz, 3 H), 1.07 (t, J=7.8 Hz, 3 H), 1.23 (t, J=7.8 Hz, 3 H), 1.34 (t, J=7.8 Hz, 3 H), 1.46 (m, 2 H), 1.77 (m, 2 H), 2.72 (q, J=7.8 Hz, 2 H), 2.86 (q, J=7.8 Hz, 2 H), 3.13 (t, J=6.9 Hz, 2 H), 4.04 (t, J=6.9 Hz, 2 H), 7.37 (m, 2 H), 7.48 (m, 1 H), 7.62 (s, 1 H). MS (CI/NH₃): m/z 434 (M⁺(C₂₃H₂₈ ³⁵ClNO₃S)+1, base), 404 (M⁺−C₂H₅), 358 (M⁺−PrS).

5-Ethyl 2-propyl-4-ethyl-3-(ethylsulfanylcarbonyl)-6-phenylpyridine-5-carboxylate (55)

¹H MNR d: 0.99 (t, J=6.9 Hz, 6 H), 1.23 (t, J=7.8 Hz, 3 H), 1.41 (t, J=7.8 Hz, 3 H), 1.82 (m, 2 H), 2.72 (q, J=6.9 Hz, 2 H), 2.81 (q, J=6.9 Hz, 2 H, 3.14 (q, J=7.8 Hz, 2 H), 4.10 (q, J=7.8 Hz, 2 H), 7.40-7.44 (m, 3 H), 7.57-7.60 (m, 2 H). MS (EI): m/z 385 (M⁺), 340 (M⁺−OEt), 324 (M⁺−SEt), 296 (M⁺−COSEt).

5-Ethyl 2-(2-methoxylethyl)-4-ethyl-3-(ethylsulfanylcarbonyl)-6-phenylpyridine-5-carboxylate (56)

¹H NMR d: 0.99 (t, J=7.8 Hz, 3 H), 1.23 (t, J=7.8 Hz, 3 H), 1.41 (t, J=7.8 Hz, 3 H), 2.73 (q, J=7.8 Hz, 2 H), 3.11-3.18 (m, 4 H), 3.37 (s, 3 H), 3.8 (t, J=7.8 Hz, 2 H), 4.10 (q, J=7.8 Hz, 2 H), 7.42-7.44 (m, 3 H), 7.5 8-7.61 (m, 2 H). MS (CI/NH₃): m/z 402 (MH⁺, base). HRMS: calcd. for CH₂₂H₂₇NO₄S 401.1661, found 401.1666.

5-Ethyl 2-butyl-4-ethyl-3-(ethylsulfanylcarbonyl)-6-phenylpyridine-5-carboxylate (57)

¹H NMR d: 0.93 (t, J=7.8 Hz, 3 H), 0.99 (t, J=7.8 Hz, 3 H), 1.23 (t, J=7.8 Hz, 3 H), 1.28-1.39 (m, 2 H), 1.41 (t, J=7.8 Hz, 3 H), 1.77 (m, 2 H), 2.72 (q, J=7.8 Hz, 2 H), 2.83 (t, J=7.8 Hz, 2 H), 3.13 (q, J=7.8 Hz, 2 H), 4.10 (q, J=7.8 Hz, 2 H), 7.40-7.43 (m, 3 H), 7.58-7.60 (m, 2 H). MS(CI/NH₃): m/z 400 (M⁺+1, base). MS (EI): m/z 400 (M⁺+1), 371 (MH⁺−Et), 338 (M⁺−SEt, base). HRMS: calcd. for C₂₃H₂₉NO₃S 399.1868, found 399.1867.

5-Ethyl 2-cyclobutyl-4-ethyl-3-(ethylsulfanylcarbonyl)-6-phenylpyridine-5-carboxylate (58)

¹H NMR d: 1.00 (t, J=7.8 Hz, 3 H), 1.21 (t, J=7.8 Hz, 3 H), 1.42 (t, J=7.8 Hz, 3 H), 1.86-1.95 (m, 1 H), 1.95-2.05 (m, 1 H), 2.17-2.56 (m, 2 H), 2.51-2.64 (m, 2 H), 2.70 (q, J=7.8 Hz, 2 H), 3.13 (q, J=7.8 Hz, 2 H), 3.79 (m, 1 H), 4.11 (q, J=7.8 Hz, 2 H), 7.42-7.44 (m, 3 H), 7.67-7.69 (m, 2 H). MS(CI/NH₃): m/z 398 (M⁺+1, base).

EXAMPLE 6

This Example illustrates the analytical data of dihydropyridines and pyridines of the present invention. The elemental analysis, the mass spectral data and the yield data obtained are set forth in Table 1.

TABLE 1 The elemental analysis, high resolution mass spectra (HRMS), and the synthetic yield data for certain dihydropyridine and pyridine derivatives. Calculated (%) Found (%) Compound Formula MW C H N C H N Yield (%) 60 C₂₀H₂₅NO₄ + 0.25H₂O 343.41 69.04 7.39 4.04 68.72 7.21 3.94 63 61 C₂₀H₂₅NO₄ 343.41 69.95 7.34 4.08 69.65 7.39 3.99 55 62 C₂₀H₂₅NO₃S 359.48 66.82 7.01 3.90 66.78 7.08 3.80 81 63 C₂₁H₂₇NO₄S 389.50 64.75 6.99 3.60 64.72 7.16 3.43 68 64 C₂₁H₂₇NO₃S + 0.1H₂O 375.31 67.20 7.31 3.58 67.11 7.39 3.58 54 65 C₂₅H₂₇NO₃S 421.54 71.23 6.46 3.32 71.11 6.43 3.40 47 66 C₂₁H₂₇NO₆ 389.44 64.76 6.99 3.60 66.58 6.25 3.97 30 67^(a) C₁₉H₂₁NO₅ 343.37 HRMS (M⁺-CHO): 314.1392 314.1432 82 70 C₂₈H₂₇NO₄ + 0.5C₃H₆O 470.54 75.29 6.43 2.98 75.32 6.31 3.31 24 71 C₂₉H₂₉NO₄ + 0.2H₂O 459.13 75.86 6.45 3.05 75.95 6.48 3.01 35 72 C₃₀H₃₁NO₄ 469.56 76.73 6.65 2.98 76.46 6.60 2.83 16 73 C₃₁H₃₃NO₄ 483.60 76.99 6.88 2.90 76.73 6.97 2.86 52 74 C₂₀H₂₅NO₄ 343.41 69.95 7.34 4.08 69.99 7.42 4.05 58 75 C₂₁H₂₇NO₃S 373.51 67.52 7.29 3.75 67.44 7.37 3.59 72 76 C₂₂H₂₉NO₃S 387.53 68.18 7.54 3.61 68.17 7.32 3.60 45 34^(b) C₂₀H₂₃NO₄ 341.39 HRMS(M⁺): 341.1627 341.1635 78 35^(c) C₂₀H₂₃NO₄ 341.39 HRMS(M⁺): 341.1627 341.1615 85 36 C₂₀H₂₃NO₃S 357.46 67.20 6.49 3.92 67.13 6.58 4.32 61 37 C₂₁H₂₅NO₄S 387.48 65.09 6.50 3.62 65.11 6.71 3.54 65 38 C₂₁H₂₅NO₃S 371.49 67.89 6.78 3.77 68.01 6.75 3.66 78 39 C₂₅H₂₅NO₃S 419.53 71.57 6.01 3.34 71.30 6.11 3.23 82 40^(d) C₂₁H₂₅NO₆ 387.42 HRMS(M⁺): 387.1682 387.1674 59 41 C₁₉H₁₉NO₅ + 0.4C₇H₈ 378.21 70.25 6.05 3.53 70.18 6.01 4.20 55 44 C₂₉H₂₇NO₄ 453.51 76.80 6.00 3.09 76.61 6.09 3.04 83 45 C₃₀H₂₉NO₄ 467.54 77.06 6.25 3.00 77.03 6.26 2.98 34 46^(e) C₂₀H₂₃NO₄ 341.39 HRMS(M⁺): 341.1627 341.1631 96 47 C₁₈H₁₉NO₄ + 0.1C₇H₈ 322.56 69.63 6.19 4.34 69.94 6.58 4.10 56 48 C₂₁H₂₅NO₃S 371.49 67.89 6.78 3.77 68.07 6.94 3.66 39 49a C₂₂H₂₇NO₃S 385.52 68.54 7.06 3.63 70.16 7.25 3.35 85 49b C₂₃H₂₉NO₃S 399.54 69.14 7.32 3.51 68.86 7.25 3.61 71 50 C₂₁H₂₅NO₄S 387.49 65.09 6.50 3.62 64.91 6.47 3.46 54 51 C₂₁H₂₄ClNO₃S + 0.1C₇H₈ 415.14 62.78 5.85 3.37 62.98 6.04 3.23 58 52^(f) C₂₀H₂₉NO₃S 363.51 HRMS(M⁺): 363.1868 363.1858 52 53 C₂₂H₂₇NO₃S + 0.1H₂O 387.32 68.22 7.08 3.62 68.14 7.15 3.53 79 54 C₂₃H₂₈ClNO₃S 433.98 63.65 6.50 3.23 63.40 6.53 3.08 65 55 C₂₂H₂₇NO₃S 385.51 68.54 7.06 3.63 68.48 7.33 3.41 51 56^(g) C₂₂H₂₇NO₄S 401.51 HRMS(M⁺): 401.1661 401.1666 65 57^(h) C₂₃H₂₉NO₃S 399.54 HRMS(M⁺): 399.1868 399.1867 53 58 C₂₃H₂₇NO₃S + 0.6H₂O 408.33 67.65 6.96 3.43 67.77 6.70 3.23 64 The following compounds were shown to be pure on analytical TLC (silica gel 60, 250 μm) EtOAc-Petroleum ether = 10:90 (v/v), unless otherwise noted. The R_(f) values are set forth below: ^(a)Compound 67, R_(f) = 0.87 ^(b)Compound 34, R_(f) = 0.44 ^(c)Compound 35, R_(f) = 0.35 ^(d)Compound 40, EtOAc-petroleum ether = 20:80 (v/v), R_(f) = 0.36 ^(e)Compound 46, R_(f) = 0.46 ^(f)Compound 52, R_(f) = 0.51 ^(g)Compound 56, R_(f) = 0.27 ^(h)Compound 57, R_(f) = 0.54

EXAMPLE 7

This Example illustrates a procedure for the preparation of β-amino-α,β-unsaturated esters which are intennediates in the synthesis of the pyridines and dihydropyridines of the present invention. The reactions involved are schematically shown in FIG. 6.

A β-ketoester (3 mmol) and ammonium acetate (4.5 mmol) were mixed in 5 mL of absolute ethanol and refluxed at 80° C. for 24 h. The solvent was removed, and the residue was chromatographed to give the desired compounds in moderate yields. The ¹HNMR and high resolution mass spectral data of the β-enaminoesters are set forth below.

Ethyl 3-amino-3-phenyl-2-propenoate (77a)

¹H NMR d: 1.30 (t, J=6.9 Hz, 3 H), 4 18 (q, J=6.9 Hz, 2 H) 4.97 (s, 1 H), 7.41-7.53 (m, 3 H), 7.54-7.57 (m, 2 H).

Benzyl 3-amino-3-phenyl-2-propenoate (77b)

¹H NMR d: 4.97 (s, 1/4 H), 5.05 (s, 3/4 H), 5.18 (s, 2 H), 7.29-7.56 (m, 10 H). MS(CI/NH₃): m/z 272 (M⁺+NH₄), 254 (M⁺+1, base).

Propyl 3-amino-3-phenyl-2-propenoate (77d)

¹H NMR d: 0.98 (t, J=7.8 Hz, 3 H), 1.70 (m, 2 H), 4.09 (t, J=7.8 Hz, 2 H), 4.99 (s, 1 H), 7.39-7.44 (m, 3 H), 7.54-7.57 (m, 2 H). MS(CI/NH₃): m/z 206 (M⁺+1, base).

Hydroxyethyl 3-amino-3-phenyl-2-propenoate (77e)

¹H NMR d: 3.87 (m, 2 H), 4.28 (m, 2 H), 5.02 (s, 1 H), 7.43-7.47 (m, 3 H), 7.54-7.57 (m, 2 H). MS(CI/NH₃): m/z 208 (M⁺+1, base), 192 (M⁺−NH₂).

Ethyl 3-amino-3-(m-chlorophenyl)-2-propenoate (77f)

¹H NMR d: 1.30 (t, J=6.9 Hz, 3 H), 4.18 (q, J=6.9 Hz, 2 H), 4.95 (s, 1 H), 7.35-7.44 (m, 3 H), 7.54 (s, 1 H). MS(CI/NH₃): m/z 226 (C₁₁H₁₂ ³⁵ClNO₂, M⁺+1, base), 227 (M⁺, C₁₁H₁₂ ³⁷ClNO₂).

Ethyl 3-amino-3-cyclopentyl-2-propenoate (77g)

¹H NMR d: 1.27 (t, J=6.9 Hz, 3 H), 1.54-1.81 (m, 6 H), 1.89-1.94 (m, 2 H), 2.50 (m, 1 H), 4.11 (q, J=6.9 Hz, 2 H), 4.60 (s, 1 H). MS(CI/NH₃): m/z 184 (M⁺+1, base).

Propyl 3-amino-3-(m-chlorophenyl)-2-propenoate (77h)

¹H NMR d: 0.98 (t, J=6.9 Hz, 3 H), 1.69 (m, 2 H), 4.09 (q, J=6.9 Hz, 2 H), 4.96 (s. 1 H), 7.32-7.45 (m, 3 H), 7.54 (s, 1 H). MS(CI/NH₃): m/z 240 (C₁₂H₁₄ ³⁵ClNO₂, M⁺+1, base). MS(EI): m/z 239 (M⁺), 223 (M⁺−NH₂), 180 (M⁺−PrO), 153 (M⁺−1−CO₂Pr, base).

EXAMPLE 8

This Example illustrates a method of preparation of 2,2-dimethoxyacetaldehyde (78d), which is an intermediate in the preparation of the pyridines and dihydropyridines of the present invention. This compound was prepared using a published procedure with some modifications. E. J. Witzemann et al., Org. Synth. Coll. II, 307-308 (1943).

Potassium permanganate (16 g, 100 mmol) in 300 mL of water was added slowly to a vigorously stirred ice-cooled suspension of 10.2 g (100 mmol) of acrolein dimethyl acetal in 120 mL of water. The speed of addition was controlled to keep the temperature as near to 5° C. as possible. Soon after the stirring stopped, the mixture formed a gel. After standing for 2 h, the mixture was heated at 95° C. for 1 h and then filtered. Upon cooling, the filtrate was treated with 240 g of anhydrous K₂CO₃. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate (80 mL×5). Organic phases were combined and dried with anhydrous MgSO₄. After removing the solvent, a colorless oil (6.84 g, yield: 50%) remained which was identified as dl-glyceraldehyde dimethyl acetal (83): ¹H NMR d: 2.44 (s, br, 1 H), 2.73 (s, br, 1 H), 3.48 (s, 6 H), 3.69-3.73 (m, 3 H), 4.36 (d, J=6.0 Hz, 1 H). MS(CI/NH₃): m/z 154 (M⁺+NH₄, base).

Compound 83 (2.11 g, 15.5 mmol) was dissolved in a mixture of dichloromethane (100 mL) and water (5 mL), and cooled to 0° C. While stirring, sodium periodate (7.5 g, 35 mmol) was carefully added in three portions within 30 min. After stirring for an additional 1 h at room temperature, anhydrous MgSO₄ (14 g) was added to the reaction mixture, and stirring was continued for an additional 0.5 h. The reaction was then filtered. Removal of the solvent left 1.38 g of the desired product 78d, yield: 85%. ¹H NMR: δ3.46 (s, 6 H), 4.50 (d, J=1.8 Hz, 1 H), 9.48 (d, J=1.8 Hz, 1 H).

EXAMPLE 9

This Example illustrates a method for the synthesis of β-ketoesters 79c, 79d, 79g, 79j-k, and 79u which are intermediates in the preparation of pyridines and dihydropyridines of the present invention. β-Ketoester 79c and β-ketothioesters 79d and 79g were prepared by the reaction of 2,2,6-trimethyl-4H-1,3-dioxin-4-one (84) and an alcohol or a thiol, shown schematically in FIG. 8. Equimolar amounts (for example, 3 mmol) of compound 84 and an alcohol or a thiol were heated with a little toluene (1-2 mL) at 100° C. in a sealed tube overnight. After being cooled to room temperature, the solvent was removed under reduced pressure and the residue was chromatographed to give the desired products in satisfactory yields (64% for 79c, 97% for 79d, and 67% for 79g). The NMR and mass spectral data are set forth below.

Propyl acetoacetate (79c)

¹H NMR d: 0.94 (t, J=6.9 Hz, 3 H), 1.66 (m, 2 H), 2.27 (s, 3 H), 3.46 (s, 2 H), 4.09 (t, J=6.9 Hz, 2 H).

S-Ethyl 3-oxothiobutyrate (79d)

¹H NMR d: 1.28 (t, J=7.8 Hz, 3 H), 2.27 (s, 3 H), 2.94 (q, J=7.8 Hz, 2 H), 3.67 (s, 2 H).

S-(2-Methoxyethyl) 3-oxothiobutyrate (79g)

¹H NMR d: 2.27 (s, 3 H), 3.15 (t, J=6.0 Hz, 2 H), 3.37 (s, 3 H), 3.55 (t, J=6.0 Hz, 2 H), 3.69 (s, 2 H). MS (CI/NH₃): 194 (M⁺+NH₄, base), 176 (M⁺).

β-Ketoesters 79j and 79k were prepared by a route shown schematically in FIG. 9. N-Isopropylcyclohexylamine (0.786 g, 5.5 mmol) and n-BuLi (2.2 mL, 5.5 mmol, 2.5 N in hexanes) were mixed at 0° C. in 15 mL of THF for 15 min. The temperature was then lowered to −78° C. Benzyl acetate (0.752 g, 0.72 mL, 5 mmol) was then added slowly into this system and stirred for 10 min at the same temperature to form an enolate. Cyclohexanecarbonyl chloride (0.806 g, 0.74 mL, 5.5 mL, for 79k) or cyclopentanecarbonyl chloride (0.729 g, 0.67 mL, 5.5 mmol, for 79j) was added dropwise to this enolate solution within 10 min. After stirring for 15 min, the reaction mixture was allowed to warm to room temperature and poured into 10 mL of 1 N HCl. The organic phase was separated, and the aqueous phase was extracted with ether (10 mL×3). The combined organic phases were washed with 1 N NaHCO₃ (10 ml) and water (10 mL), and then dried with arhydrous MgSO₄. The solvent was removed, and the residue was chromatographed (silica 60, petroleum ether-ethyl acetate (9:1)) to give 130 mg of 79k (yield: 10%) or 569 mg of 79j (yield: 46%). The NMR data are set fort below.

Benzyl 3-oxo-3-clopentylpropionate (79j)

¹H NMR d: 1.19-1.81 (m, 8 H), 2.76-2.85 (m, 1 H), 3.55 (s, 2 H), 5.11 (s, 2 H), 7.31-7.36 (m, 5 H).

Benzyl 3-oxo-3-cyclohexylproionate (79k)

¹H NMR d: 1.20-1.51 (m, 5 H), 1.66-1.96 (m, 5 H), 2.25-2.38 (m, 1 H), 3.51 (s, 2 H), 5.19 (s, 2 H), 7.37 (m, 5 H).

To prepare compound 79u, a transesterification reaction shown schematically in FIG. 10 was used. Ethyl benzoylacetate (1.92 g, 10 mmol) and ethylene glycol (0.621 g, 10 mmol) in toluene (10 mL) were heated with stirring for 24 h. The solvent was removed, and the residue was chromatographed (silica 60, petroleum ether-ethyl acetate (3:1)) to give 0.946 g of the desired product, yield: 45%. The ¹HNMR data are set forth below.

Hydroxyethyl benzoylacetate (79u)

¹H NMR d: 2.52 (s, br, 1 H), 3.4 (m, 2 H), 4.08 (s, 2 H), 4.35 (t, J=7.8 Hz, 2 H), 7.43-7.53 (m, 2 H), 7.60-7.65 (m, 1 H), 7.93-7.96 (m, 2 H).

EXAMPLE 10

This Example illustrates a method of preparation of the β-ketoesters 79e-f, 79h-i, 79e-n, and 79p-t via Meldrum's acids, shown schematically in FIG. 11. Oikawa et al., J. Org. Chem., 43, 2087-2088 (1978).

The preparation of S-ethyl 3-oxothiovalerate (79e) is provided here as an example. 2,2-Dimethyl-1,3-dioxane-4,6-dione (86, 0.721 g, 5 mmol) and propionyl chloride (0.509 g, 5.5 mmol) were dissolved in 10 mL of dry CH₂Cl₂. At 0° C., 0.81 mL (0.791 g, 10 mmol) of pyridine (in the cases of aromatic acid chlorides, using 4-dimethylaminopyridine instead of pyridine) was then added dropwise. The reaction temperature was kept at 0° C. for 1 h, and then raised to room temperature for an additional 1 h. The reaction mixture was then washed with 1 N HCl (10 mL) and water (5 mL), and then dried with anhydrous MgSO₄. Removal of the solvent yielded the desired product (87e), which was directly used for the next reaction without further purification.

Compound 87e (670 mg, 3.35 mmol) and ethanethiol (0.621 g, 10 mmol) were mixed in 10 mL of toluene. This mixture was heated at 80° C. in a flask with an effective flux condenser for 24 h. The solvent and excess ethanethiol were removed, and the residue was chromatographed (silica 60, petroleum ether-ethyl acetate (9:1)) to give the desired product 282 mg, yield: 53%. The NMR and mass spectral data are set forth below:

S-Ethyl 3-oxothiovalerate (79e)

¹H NMR d: 1.07 (t, J=6.9 Hz, 3 H), 1.28 (t, J=6.9 Hz, 3 H), 2.58 (q, J=6.9 Hz, 2 H), 2.94 (q, J=6.9 Hz, 2 H), 3.66 (s, 2 H). MS (CI/NH₄): m/z 178 (M⁺+NH₄), 161 (M⁺+1).

S-Ethyl 3-oxothiocaproate (79f)

¹H NMR d: 0.92 (t, J=7.8 Hz, 3 H), 1.28 (t, J=7.8 Hz, 3 H), 1.62 (m, 2 H), 2.53 (t, J=6.9 Hz, 2 H), 2.93 (q, J=7.8 Hz, 2 H), 3.65 (s, 2 H). MS (CI/NH₄): m/z 192 (M⁺+NH₄, base), 175 (M⁺+1).

Benzyl 3-oxo-3-cyclopropylpropionate (79h)

¹H NMR d: 0.90-0.96 (m, 2 H), 1.08-1.13 (m, 2 H), 1.98-2.05 (m, 1 H), 3.62 (s, 2 H), 5.20 (s, 2 H), 7.30-7.39 (m, 5 H). MS (CI/NH₄): m/z 236 (M⁺+NH₄, base), 219 (M⁺+1).

Benzyl 3-oxo-3-cyclobutylpropionate (79i)

¹H NMR d: 1.59-2.37 (m, 6 H), 3.37 (m, 1 H), 3.45 (s, 2 H), 5.17 (s, 2 H), 7.34-7.37 (m, 5 H). MS (CI/NH₄): m/z 250 (M⁺+NH₄, base), 233 (M⁺+1).

S-Ethyl 3-oxothioheptanoate (79 l)

¹H NMR d: 0.91 (t, J=7.8 Hz, 3 H), 1.28 (t, J=7.8 Hz, 3 H), 1.51-1.62 (m, 4 H), 2.55 (t, J=7.8 Hz, 2 H), 2.93 (q, J=7.8 Hz, 2 H), 3.65 (s, 2 H). MS (CI/NH₄): m/z 206 (M⁺+NH₄, base).

S-Propyl 3-oxothiovalerate (79m)

¹H NMR d: 0.98 (t, J=6.9 Hz, 3 H), 1.07 (t, J=7.8 Hz, 3 H), 1.62 (m, 2 H), 2.58 (q, J=6.9 Hz, 2 H), 2.91 (t, J=7.8 Hz, 2 H), 3.67 (s, 2 H). MS (CI/NH₄): m/z 175 (M⁺+1).

S-Ethyl 3-oxo-3-cyclobutylthiopropionate (79n)

¹H NMR d: 1.27 (t, J=7.8 Hz, 3 H), 1.85 (m, 1 H), 1.93-2.05 (m, 1 H), 2.14-2.31 (m, 4 H), 2.92 (q, J=7.8 Hz, 2 H), 3.42 (m, 1 H), 3.61 (s, 2 H). MS (CI/NH₄): m/z 204 (M⁺+NH₄, base), 187 (M⁺+1).

S-Ethyl 3-oxo-5-methoxythiovalerate (79p)

¹H NMR d: 1.28 (t, J=7.8 Hz, 3 H), 2.80 (t, J=6.0 Hz, 2 H), 2.93 (q, J=7.8 Hz, 2 H), 3.34 (s, 3 H), 3.65 (t, J=6.0 Hz, 2 H), 3.71 (s, 2 H). MS (CI/NH₄): m/z 208 (M⁺+NH₄, base), 191 (M⁺+1).

Ethyl 3-oxo-3-cyclopentylpropionate (79q)

¹H NMR d: 1.28 (t, J=7.8 Hz, 3 H), 1.59-1.71 (m, 2 H), 1.76-1.88 (m, 2 H), 2.98 (m, 1 H), 3.49 (s, 2 H), 4.19 (q, J=7.8 Hz, 2 H). MS (CI/NH₄): m/z 202 (M⁺+NH₄, base).

Propyl benzoylacetate (79r)

¹H NMR d: 0.95 (t, J=6.9 Hz, 3 H), 1.64-1.71 (m, 2 H), 3.39 (s, 2 H), 4.12 (t, J=6.9 Hz, 2 H), 7.47-7.97 (m, 5 H). MS (CI/NH₄): m/z 224 (M⁺+NH₄, base), 206 (M⁺).

Ethyl m-chlorobenzoylacetate (79s)

¹H NMR d: 1.26 (t, J=6.9 Hz, 3 H), 3.91 (s, 2 H), 4.22 (t, J=6.9 Hz, 2 H), 7.36-7.84 (m, 3 H), 7.93 (s, 1 H). MS (CI/NH₄): m/z 244 (C₁₁H₁₁ ³⁵ClO₃, M⁺+NH₄, base), 227 (C₁₁H₁₁ ³⁵ClO₃, M⁺+1).

Propyl m-chlorobenzoylacetate (79t)

¹H NMR d: 0.90 (t, J=7.8 Hz, 3 H), 1.64 (m, 2 H), 3.98 (s, 2 H), 4.12 (t, J=6.9 Hz, 2 H), 7.36-7.84 (m, 3 H), 7.93 (s, 1 H). MS (CI/NH₄): m/z 258 (C₁₁H₁₁ ³⁵ClO₃, M⁺+NH₄, base), 241 (C₁₁H₁₁ ³⁵ClO₃, M⁺+1).

EXAMPLE 11

This Example illustrates the A₁, A₂, and A₃ adenosine receptor binding affinities of certain pyridine derivatives of the present invention. The affinities were determined in radioligand binding assays and the results thereof are set forth in Table 2.

TABLE 2 Affinities of Pyridine derivatives in radioligand binding assays at A₁, A_(2A), and A₃ adenosine receptors.

Compound R₂ R₃ R₄ R₅ R₆ rA₁a rA_(2A)b hA₃c rA₁/hA₃ 1 CH₂CH₃ SCH₂CH₃ CH₂CH₃ CH₂CH₃ Ph 41 ± 6% (10⁻⁴) 6130 ± 1280 20.0 ± 1.9 >3000 2 CH₂CH₃ SCH₂CH₃ CH₂CH₂CH₃ CH₂CH₂CH₃ Ph 15600 ± 6900 2050 ± 440 18.9 ± 4.1 7400 3 CH₂CH₃ SCH₂CH₃ CH₂CH₃ CH₂CH₂f Ph 11,500 ± 2900 ˜7000 4.22 ± 0.66 2700 4 CH₂CH₃ SCH₂CH₃ CH₂CH₂N-Pth CH₂CH₃ Ph 490 ± 48 4250 200 — 5 CH₂CH₃ SCH₂CH₃ CH₂CH₂CH₂N-Pth CH₂CH₃ Ph 5240 ± 1760 d (10⁻⁴) 28% (10⁻⁶) — 6 CH₂CH₃ SCH₂CH₃ CH₂CH₃ CH₂CH₂CH₃ Ph 7770 ± 1830 d (10⁻⁵) 8.29 ± 1.15 8.20 7 CH₂CH₃ S(CH₂)₃CH₃ CH₂CH₃ CH₂CH₂CH₃ 3-Cl—Ph 113,000 ± 28,000 d (10⁻⁴) 18.9 ± 4.1 7400 8 CH₂CH₂OH SCH₂CH₃ CH₂CH₂CH₃ CH₂CH₂CH₃ Ph 5940 ± 930 ˜20,000 >100,000 — 9 CH₂CH₂OBn SCH₂CH₃ CH₂CH₂CH₃ CH₂CH₂CH₃ Ph 16,000 ± 1400 7000 109 ± 1 160 10 CH₂CH₂F SCH₂CH₃ CH₂CH₂CH₃ CH₂CH₂CH₃ Ph 19,800 ± 1100 ˜30,000 2.88 — 11 CH₂CH₂SCOCH₃ SCH₂CH₃ CH₂CH₂CH₃ CH₂CH₃ Ph 12,200 ± 2200 6000 8 — 12 CH₂CH₃ SCH₂CH₂OH CH₂CH₂CH₃ CH₂CR₂CH₃ Ph 10,800 ± 2800 5590 ± 2000 51.1 ± 13.3 210 13 CH₂CH₃ SCH₂CH₂OTHP CH₂CH₂CH₃ CH₂CH₂CH₃ Ph 18 ± 1% (10⁻⁴) d (10⁻⁴) 517 ± 151 >20 (rac) 14 CH₂CH₃ SCH₂-(2,2- CH₂CH₂CH₃ CH₂CH₂CH₃ Ph 5710 ± 1150 d (10⁻⁴) 3000 — dimethyl-1,3- dioxolane) (rac) 15 CH₂CH₃ SCH₂CH₂F CH₂CH₂CH₃ CH₂CH₂CH₃ Ph 8220 ± 3250 ˜24,000 55.1 ± 8.2 150 16 CH₂CH₃ SCH₂CF₃ CH₂CH₂CH₃ CH₂CH₂CH₃ Ph 8290 ± 2350 6140 ± 1850 18.1 ± 2.2 460 17 CH₂CH₃ SCH₂CH₃CH₂F CH₂CH₂CH₃ CH₂CH₂CH₃ Ph 12,600 ± 2800 d (10⁻⁴) 1100 — 18 CH₂CH₃ SCH₂CH₂OH CH₂CH₂OH₃ CH₂CH₂CH₃ Ph 9010 ± 1890 — 2200 — 19 CH₂CH₃ SCH₂CH₃ CH₂CH₂SCOCH₃ CH₂CH₂CH₃ Ph 9800 ± 3490 4000 100 — 20 CH₂CH₃ SCH₂CH₃ CH₂CH₂F CH₂CH₂CH₃ Ph — — — — 21 CH₂CH₃ SCH₂CH₃ CH₂CH₂CH₂F CH₂CH₂CH₃ Ph 8090 ± 1040 20,000 20 — 22 CH₂CH₃ SCH₂CH₃ CH₂CH₂CH₂OH CH₂CH₂CH₃ Ph 9060 ± 2950 8760 ± 2490 169 ± 61 54 23 CH₂CH₃ SCH₂CH₃ CH₂CH₂CH₃ CH₂CH₂CH₂F Ph 6050 ± 1360 9670 ± 3340 9.67 ± 3.34 630 24 CH₂CH₃ SCH₂CH₃ CH₂CH₂CH₃ CH₂CF₂CF₃ Ph 5680 ± 920 15,400 446 ± 119 13 25 CH₂CH₃ SCH₂CH₃ CH₂CH₂CH₃ CH₂CH₂CH₃ 2-F-Ph 13,500 ± 1600 8630 ± 3550 23.0 ± 6.8 590 26 CH₂CH₃ SCH₂CH₃ CH₂CH₂CH₃ CH₂CH₂CH₃ 3-F-Ph 8200 ± 810 28,100 ± 10,900 28.9 ± 10.8 280 27 CH₂CH₃ SCH₂CH₃ CH₂CH₂CH₃ CH₂CH₂CH₃ 4-F-Ph 12,300 50% (10⁻⁴) 31.1 ± 9.24 ˜400 28^(f) CH₂CH₃ SCH₂CH₃ CH₂CH₂CH₃ CH₂CH₂CH₃ Ph — — — — 29^(e) CH₂CH₃ cyclized to R₄ CH₂CH₂O— CH₂CH₂CH₃ Ph 11,200 ± 2500 8000 d (10⁻⁴) — as a lactone 30^(e) CH₂CH₃ cyclized to R₄ CH₂CH₂CH₂NH— CH₂CH₃ Ph 5790 ± 480 d (10⁻⁴) 2000 — as a lactone 31^(e) CH₂CH₃ cyclized to R₄ CH₂CH₂S— CH₂CH₂CH₃ Ph 26,000 — 200 — as a thiolactone 32^(e) —CH₂CH₂— cycilzed to R₂ CH₂CH₂CH₃ CH₂CH₃ Ph 25,100 ± 5900 — 12%(10⁻⁴) — as thiolactone 33^(e) CH₃ OCH₂CH₃ CH₃ CH₂CH₃ Ph 7.41 ± 1.29 28.4 ± 9.1 4.47 ± 0.46 1.7 34 CH₃ OCH₂CH₂CH₃ CH₃ CH₂CH₃ Ph 5.05 ± 0.54 24.5 ± 8.5 0.215 ± 0.022 23 35 CH₃ OCH₂CH₃ CH₂CH₃ CH₂CH₃ Ph 3.36 ± 0.60 3.69 ± 1.25 0.176 ± 0.038 19 36 CH₃ SCH₂CH₃ CH₂CH₃ CH₂CH₃ Ph 14.8 ± 3.5 14.9 ± 4.1 0.0429 ± 0.0088 340 37 CH₃ SCH₂CH₂OCH₃ CH₂CH₃ CH₂CH₃ Ph 36 ± 11% (10⁻⁴) 7.98 ± 1.36 0.165 ± 0.012 >500 38 CH₃ SCH₂CH₃ CH₂CH₂CH₃ CH₂CH₃ Ph 29 ± 6% (10⁻⁴) 7.53 ± 2.70 0.194 ± 0.051 >700 39 CH₃ SCH₂CH₃ CH₂CH₃ CH₂Ph Ph 20 ± 8% (10⁻⁴) 12.8 ± 2.9 2.61 ± 0.96 >40 40 CH₃ OCH₂CH₃ CH(OCH₃)₂ CH₂CH₃ Ph 1.95 ± 0.43 2.88 ± 0.61 0.783 ± 0.154 2.5 41 CH₃ OCH₂CH₃ CHO CH₂CH₃ Ph 9.56 ± 4.09 2.56 ± 0.13 — — 42 CH₃ OCH₂CH₃ Ph—CH═CH— CH₂CH₃ Ph 2.49 ± 0.47 2.40 ± 0.22 2.80 ± 1.78 0.85 (trans) 43 CH₃ OCH₂CH₃ Ph—C≡C— CH₂Ph Ph 11.6 ± 4.8 43 ± 20% (10⁻⁴) 2.75 ± 0.78 4.2 44 CH₃ OCH₂CH₃ Ph—C≡C— CH₂Ph cylobutyl d (10⁻⁴) 27.6 ± 12.0 2.41 ± 0.59 >40 45 CH₃ OCH₂CH₃ Ph—C≡C— CH₂Ph cyclopentyl 56.2 ± 20.8 22.9 ± 5.0 3.85 ± 0.79 15 46 CH₂CH₃ OCH₂CH₃ CH₃ CH₂CH₃ Ph 10.3 ± 1.7 13.4 ± 4.2 0.121 ± 0.008 85 47 CH₂CH₃ OH CH₂CH₃ CH₂CH₃ Ph 4.25 ± 0.65 7.09 ± 0 97 30% (10⁻⁴) <1 48 CH₂CH₃ SCH₂CH₃ CH₂CH₃ CH₂CH₃ Ph 41 ± 6% (10⁻⁴) 6.13 ± 1.28 0.0200 ± 0.0019 >3000 49a CH₂CH₃ SCH₂CH₃ CH₂CH₃ CH₂CH₂CH₃ Ph 7.77 ± 1.83 d (10⁻⁵) 0.00829 ± 940 0.00115 49b CH₂CH₃ SCH₂CH₃ CH₂CH₂CH₃ CH₂CH₂CH₃ Ph 18.2 ± 9.0 d (10⁻⁴) 0.0245 ± 0.0040 7400 50 CH₂CH₃ SCH₂CH₃ CH₂CH₃ CH₂CH₂OH Ph 17.4 ± 5.29 10.0 ± 3.0 0.188 ± 0.061 93 51 CH₂CH₃ SCH₂CH₃ CH₂CH₃ CH₂CH₃ 3-Cl—Ph 8.20 ± 2.96 8.91 ± 0.97 0.0134 ± 0.0015 610 52 CH₂CH₃ SCH₂CH₃ CH₂CH₃ CH₂CH₃ cyclopentyl 55.3 ± 14.7 26.1 ± 6.2 4.01 ± 2.49 14 53 CH₂CH₃ SCH₂CH₂CH₃ CH₂CH₃ CH₂CH₃ Ph 8.22 ± 1.21 15.7 ± 4.4 0.0159 ± 0.0054 520 54 CH₂CH₃ SCH₂CH₂CH₃ CH₂CH₃ CH₂CH₂CH₃ 3-Cl—Ph 41.4 ± 11.9 24.1 ± 7.9 0.00242 ± 17,000 0.00070 55 CH₂CH₂CH₃ SCH₂CH₃ CH₂CH₃ CH₂CH₃ Ph 16.7 ± 3.0 2.82 ± 0.82 0.0333 ± 0.0107 500 56 (CH₂)₂OCH₃ SCH₂CH₃ CH₂CH₃ CH₂CH₃ Ph 10.1 ± 2.1 12.6 ± 1.7 0.0168 ± 0.0020 600 57 (CH₂)3CH₃ SCH₂CH₃ CH₂CH₃ CH₂CH₃ Ph 40.3 ± 7.4 d (10⁻⁴) 0.0350 ± 0.0091 1200 58 cyclobutyl SCH₂CH₃ CH₂CH₃ CH₂CH₃ Ph 30% (10⁻⁴) 22% (10⁻⁴) 0.145 ± 0.044 >500 ^(a)Displacement of specific [³H]R - PIA binding in rat brain membranes, expressed as K_(i) ± S.E.M. in μM (n = 3-5), or as a percentage of specific binding displaced at the indicated concentration (M). ^(b)Displacement of specific [³H]CGS 21680 binding in rat striatal membranes, expressed as K_(i) ± S.E.M. in μM (n = 3-6), or as a percentage of specific binding displaced at the indicated concentration (M). ^(c)Displacement of specific [¹²⁵I]AB-MECA binding at human A₃ receptors expressed in HEK cells, in membranes, expressed as K_(i) ± S.E.M. in μM (n = 3-4). ^(d)Displacement of <10% of specific binding at the indicated concentration (M). ^(e)Formulas of these compounds arc set forth in FIG. 12. ^(f)N-1 methyl pyridinium salt

EXAMPLE 12

This Example illustrates the A₁, A₂, and A₃ adenosine receptor binding affinities of certain dihydropyridine derivatives of the present invention. The affinities were determined in radioligand binding assays, and the results thereof are set forth in Table 3.

TABLE 3 Affinities of 1,4-dihydropyridine derivatives in radioligand binding assays at A₁, A_(2A), and A₃ adenosine receptors

K_(i) (μM) or % inhibition^(d) Compound R₂ R₃ R₄ R₅ R₆ rA₁ ^(a) rA_(2A) ^(b) hA₃ ^(c) rA₁/hA₃ 59^(a) CH₃ OCH₂CH₂ CH₃ CH₂CH₃ Ph 25.9 ± 7.3 35.9 ± 15.3 7.24 ± 2.13 3.6 60 CH₃ OCH₂CH₂CH₃ CH₃ CH₂CH₃ Ph 1.74 ± 3.1 28.9 ± 4.8 2.11 ± 0.35 8.2 61 CH₃ OCH₂CH₃ CH₂CH₃ CH₂CH₃ Ph 21.9 ± 3.3 21.8 ± 7.8 2.27 ± 0.64 9.6 62 CH₃ SCH₂CH₃ CH₂CH₃ CH₂CH₃ Ph 35.4 ± 4.5 54.8 ± 18.8 2.01 ± 0.55 18 63 CH₃ SCH₂CH₂OCH₃ CH₂CH₃ CH₂CH₃ Ph 36 ± 14% 12.5 ± 2.5 4.58 ± 0.35 >10 (10⁻⁴) 64 CH₃ SCH₂CH₃ CH₂CH₂CH₃ CH₂CH₃ Ph 48 ± 5% (10⁻⁴) 29 ± 10% 2.17 ± 0.25 >20 (10⁻⁴) 65 CH₃ SCH₂CH₃ CH₂CH₃ CH₂Ph Ph 45 ± 2% (10⁻⁴) 14.3 ± 4.2 1.65 ± 0.40 >50 66 CH₃ OCH₂CH₃ CH(OCH₃₎₂ CH₂CH₃ Ph 32 ± 5% (10⁻⁴) d (10⁻⁴) 15.3 ± 3.9 >5 67 CH₃ OCH₂CH₃ CHO CH₂CH₃ Ph 26 ± 6% (10⁻⁴) 32 ± 15% 15.6 ± 5.4 >6 (10⁻⁴) 68^(a) CH₃ OCH₂CH₃ Ph—CH═CH— CH₂CH₃ Ph 5.93 ± 0.27 4.77 ± 0.29 0.108 ± 0.012 55 (trans) 69^(a) CH₃ OCH₂CH₃ Ph—C≡C— CH₂Ph Ph 40.1 ± 7.5 d (10⁻⁴) 0.0314 ± 1300 0.0028^(f) 70 CH₃ OCH₂CH₃ Ph—C≡C— CH₂Ph cyclopropyl 22 ± 1% (10⁻⁴) d (10⁻⁴) 0.0277 ± >3000 0.0024 71 CH₃ OCH₂CH₃ Ph—C≡C— CH₂Ph cyclobutyl 36 ± 8% (10⁻⁴) d (10⁻⁴) 0.0225 ± >3000 0.0030 72 CH₃ OCH₂CH₃ Ph—C≡C— CH₂Ph cyclopentyl 17.1 ± 4.3 7.16 ± 1.56 0.0505 ± 340 0.0210 73 CH₃ OCH₂CH₃ Ph—C≡C— CH₂Ph cyclohexyl 22 ± 2% (10⁻⁴) 20% (10⁻⁴) 0.229 ± 0.014 >400 74 CH₂CH₃ OCH₂CH₃ CH₃ CH₂CH₃ Ph 20 ± 4% (10⁻⁴) d (10⁻⁴) 2.83 ± 0.20 >30 75 CH₂CH₃ SCH₂CH₃ CH₂CH₃ CH₂CH₃ Ph 34 ± 7% (10⁻⁴) 29.1 ± 9.9 0.907 ± 0.044 >50 76 CH₂CH₂CH₃ SCH₂CH₃ CH₂CH₃ CH₂CH₃ Ph 26 ± 19% d (10⁻⁴) 2.09 ± 0.04 >20 (10⁻⁴) ^(a)Displacemenl of specific [³H]R - PIA binding in rat brain membranes, expressed as K_(i) ± S.E.M. in μM (n = 3-5), or as a percentage of specific binding displaced at the indicated concentration (M). ^(b)Displacement of specific [³H]CGS 21680 binding in rat striatal membranes, expressed as K_(i) ± S.E.M. in μM (n = 3-6), or as a percentage of specific binding displaced at the indicated concentration (M). ^(c)Displacement of specific [¹²⁵1]AB-MECA binding at human A₃ receptors expressed in HEK cells, in membranes expressed as K_(i) ± S.E.M. in μM (n = 3-4). ^(d)Displacement of < 10% of specific binding at the indicated concentration (M). ^(e)Values taken from A.M. van Rhee et al., J. Med. Chem., 39, 2980-2989 (1996), and Jiang et al., J. Med. Chem., 40, 2596-2608 (1997)

EXAMPLE 13

This Example illustrates the binding affinities of certain dihydropyridines and pyridine derivatives of the present invention at rat A₁ and A₃ adenosine receptors. The results obtained are set forth in Table 4, along with the ratio of affinities at rat vs. human A₃ receptors. It was found that affinity at rat A₃ adenosine receptors was generally lower than at human A₃ receptors. Certain compounds, for example, 49b, displayed high affinity at both species.

TABLE 4 Affinities of certain dihydropyridine and pyridine derivatives in radioligand binding assays at rat A₃ receptors, and comparison to rat A₁ and human A₃ adenosine receptor affinities. K_(i) (μM) Compound rA₃ ^(a) rA₁/rA₃ rA₃/hA₃ 69 1.42 ± 0.19 28 45 62 4.60 ± 0.38 7.7 2.3 64 3.10 ± 0.78 >20 1.4 65 2.80 ± 0.28 >20 1.7 71 1.75 ± 0.18 >40 78 75 2.52 ± 0.88 >30 2.8 76 2.73 ± 0.14 >30 1.3 36 1.47 ± 0.34 10 34 38 0.650 ± 0.070 >100 3.4 39 1.80 ± 0.32 >50 0.69 44 1.90 ± 0.42 >50 0.79 48 0.410 ± 0.048 >100 21 49a 0.183 ± 0.033 42 22 49b 0.113 ± 0.012 140 6.0 50 2.87 ± 0.48 6.1 15 51 0.440 ± 0.033 19 33 52 2.80 ± 0.22 >20 0.83 53 0.294 ± 0.006 28 18 54 0.814 ± 0.037 50 100 55 0.590 ± 0.040 28 18 57 2.26 ± 0.05 18 64 ^(a)Displacement of specific [¹²⁵I]AB-MECA binding at rat A₃ receptors stably expressed in CHO cells (n = 3 − 5).

All of the references cited herein including patents, patent applications, and publications, are hereby incorporated in their entireties by reference.

While this invention has been described with an emphasis upon preferred embodiments, it will be obvious to those of ordinary skill in the art that variations of the preferred embodiments may be used and that it is intended that the invention may be practiced otherwise than as specifically described herein. Accordingly, this invention includes all modifications encompassed within the spirit and scope of the invention as defined by the following claims. 

What is claimed is:
 1. A compound of the formula

or a pharmaceutically acceptable salt thereof; wherein R₂ is selected from the group consisting of C₁-C₆ alkyl, C₃-C₇ cycloalkyl, and C₁-C₆ alkoxy C₁-C₆ alkyl; R₃ is selected from the group consisting of C₁-C₆ alkylsulfanyl, hydroxy, C₁-C₆ alkoxy C₁-C₆ alkylsulfanyl, hydroxy C₁-C₆ alkylsulfanyl, and halo C₁-C₆ alkylsulfanyl, or R₃ together with R₄ forms a 3-7 membered heterocyclic ring containing O, N, or S; R₄ is selected from the group consisting of C₁-C₆ alkyl, halo C₁-C₆ alkyl, hydroxy C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ alkylsulfanyl, C₁-C₆ alkylamino, C₁-C₆ alkylcarbonyl sulfanyl C₁-C₆ alkyl, aryl C₂-C₆ alkenyl, aryl C₂-C₆ alkynyl, formyl, and acetal; R₅ is selected from the group consisting of C₁-C₆ alkyl, aryl C₁-C₆ alkyl, hydroxy C₁-C₆ alkyl, and halo C₁-C₆ alkyl; and R₆ is selected from the group consisting of aryl, C₃-C₇ cycloalkyl, and haloaryl; wherein said aryl is a phenyl or naphthyl.
 2. The compound of claim 1, wherein R₂ is selected from the group consisting of C₁-C₄ alkyl, C₄-C₅ cycloalkyl, and C₁-C₃ alkoxy C₁-C₃ alkyl; R₃ is selected from the group consisting of C₁-C₆ alkylsulfanyl, hydroxy C₁-C₃ alkylsulfanyl, and halo C₁-C₃ alkylsulfanyl; R₄ is selected from the group consising of C₁-C₃ alkyl and hydroxy C₁-C₃ alkyl; R₅ is selected from the group consisting of C₁-C₃ alkyl and halo C₁-C₃ alkyl; and R₆ is selected from the group consisting of C₄-C₆ cycloalkyl, phenyl, and halophenyl; or a pharmaceutically acceptable salt thereof.
 3. The compound of claim 2, wherein R₂ is ethyl; R₃ is selected from the group consisting of C₁-C₆ alkylsulfanyl, hydroxy C₁-C₂ alkylsulfanyl, and halo C₁-C₂ alkylsulfanyl; R₄ is selected from the group consisting of C₁-C₃ alkyl and hydroxy C₁-C₃ alkyl; R₅ is selected from the group consisting of C₁-C₃ alkyl and halo C₁-C₃ alkyl; and R₆ is selected from the group consisting of phenyl and halophenyl; or a pharmaceutically acceptable salt thereof.
 4. The compound of claim 3, wherein R₂ is ethyl; R₃ is selected from the group consisting of ethylsulfanyl, hexylsulfanyl, haloethylsulfanyl, and hydroxyethyl sulfanyl; R₄ is selected from the group consisting of ethyl, propyl, and hydroxypropyl; R₅ is selected from the group consisting of ethyl, propyl, fluoroethyl, and fluoropropyl; and R₆ is selected from the group consisting of phenyl and halophenyl; or a pharmaceutically acceptable salt thereof.
 5. The compound of claim 4, wherein R₂ is ethyl; R₃ is ethylsulfanyl; R₄ is selected from the group consisting of ethyl propyl, and hydroxypropyl; R₅ is selected from the group consisting of ethyl, propyl, fluoroethyl, and fluoropropyl; and R₆ is phenyl or fluorophenyl; or a pharmaceutically acceptable salt thereof.
 6. The compound of claim 5, wherein said compound is selected from the group consisting of 5-ethyl 2,4-diethyl 3-(ethylsulfanylcarbonyl)-6-phenylpyridine-5-carboxylate, 5-(2-fluoroethyl)-2,4-diethyl-3-(ethylsulfanylcarbonyl)-6-phenylpyridine-5-carboxylate, 5-n-propyl 2,4-diethyl-3-(ethylsulfanylcarbonyl)-6-phenylpyridine-5-carboxylate, 5-n-propyl 2-ethyl-4-n-propyl-3-(ethylsulfanylcarbonyl)-6-phenylpyridine-5-carboxylate, 5-n-propyl-2-ethyl-4-(3-hydroxy-n-propyl)-3-(ethylsulfanylcarbonyl)-6-phenylpyridine-5-carboxylate 5-(3-fluoro-n-propyl) 2-ethyl-4-n-propyl-3-ethylsulfanylcarbonyl)-6-phenylpyridine-5-carboxylate, 5-n-propyl 2-ethyl-4-n-propyl-3-(ethylsulfanylcarbonyl)-6-(2-fluorophenyl)pyridine-5-carboxylate, 5-n-propyl 2-ethyl-4-n-propyl-3-(ethylsulfanylcarbonyl)-6-(3-fluorophenyl) pyridine-5-carboxylate, and 5-n-propyl 2-ethyl-4 -n-propyl-3-(ethylsulfanylcarbonyl)-6-(4-fluorophenyl) pyridine-5-carboxylate; or a pharmaceutically acceptable salt thereof.
 7. The compound of claim 4, wherein R₂ is ethyl; R₃ is selected from the group consisting of hexylsulfanyl, haloethylsulfanyl and hydroxyethylsulfanyl; R₄ is selected from the group consisting of ethyl and propyl; R₅ is propyl; and R₆ is phenyl; or a pharmaceutically acceptable salt thereof.
 8. The compound of claim 7, wherein said compound is selected from the group consisting of 5-n-propyl 2,4-diethyl-3-(n-hexylsulfanylcarbonyl)-6-phenylpyridine-5-carboxylate, 5-n-propyl 2-ethyl-4-n-propyl-3-(2-hydroxyethylsulfanylcarbonyl)-6-phenylpyridine-5-carboxylate, 5-n-propyl 2-ethyl-4-n-propyl-3-(2-fluoroethylsulfanylcarbonyl)-6-phenyl pyridine-5-carboxylate, and 5-n-propyl 2-ethyl-4-n-propyl-3-(2,2,2-trifluoroethylsulfanylcarbonyl)-6-phenylpyridine-5-carboxylate; or a pharmaceutically acceptable salt thereof.
 9. A compound of the formula

or a pharmaceutically acceptable salt thereof; wherein R₂ is methyl; R₃ is selected from the group consisting of ethylsulfanyl, and methoxyethylsulfanyl; R₄ is selected from the group consisting of C₁-C₃ allyl and phenyl acetylenyl; R₅ is selected from the group consisting ethyl and benzyl; and R₆ is selected from the group consisting of phenyl and C₃-C₅ cycloalkyl; or a pharmaceutically acceptable salt thereof.
 10. A compound of the formula

or a pharmaceutically acceptable salt thereof, wherein R₂ is methyl; R₃ is selected from the group consisting of C₁-C₆ alkoxy, ethylsulfanyl, and methoxyethylsulfanyl; R₄ is selected from the group consisting of C₁-C₃ alkyl and phenyl acetylenyl; R₅ is selected from the group consisting ethyl and benzyl; and R₆ is selected from the group consisting of C₃-C₅ cycloalkyl; or a pharmaceutically acceptable salt thereof.
 11. A compound selected from the group consisting of 3-n-propyl 5-ethyl-2,4-dimethyl-6-phenylpyridine-3,5-dicarboxylate, 3,5-diethyl 2-methyl-4-ethyl-6-phenylpyridine-3,5-dicarboxylate, 5-ethyl 2-methyl-4ethyl-3-(ethylsulfanylcarbonyl)-6-phenylpyridine-5-carboxylate, 5-ethyl 2-methyl-4-n-propyl-3(ethylsulfanylcarbonyl)-6-phenylpyridine-5-carboxylate, 5-benzyl 2-methyl-4-ethyl-3-(ethylsulfanylcarbonyl)-6-phenylpyridine-5-carboxylate, 3-ethyl 5-benzyl-2-methyl-4-phenylethynyl-6-cyclobutylpyridine-3,5-dicarboxylate, 3-ethyl 5-benzyl-2-methyl-4-phenylethynyl-6-cyclopentylpyridine-3,5-dicarboxylate, 3-ethyl-5-benzyl-2-methyl-4-phenylethyl-6-phenylpyridine-3,5-dicarboxylate, 3,5-diethyl 2-methyl-4-(dimethoxymethyl)-6-phenylpyridine-3,5-dicarboxylate, and 3,5-diethyl 2-ethyl-4-methyl-6-phenylpyridine-3,5-dicarboxylate; or a pharmaceutically acceptable thereof.
 12. The compound of claim 1, wherein R₂ is selected from the group consisting of ethyl, propyl, butyl, cyclobutyl, and methoxyethyl; R₃ is selected from the group consisting of ethylsulfanyl and propylsulfanyl; R₄ is selected from the group consisting of methyl, ethyl, and propyl; R₅ is selected from the group consisting of ethyl, propyl, and hydroxyethyl; and R₆ is selected from the group consisting of phenyl, chlorophenyl, and cyclopentyl; or a pharmaceutically acceptable salt thereof.
 13. The compound of claim 12, wherein said compound is selected from the group consisting of 5-ethyl 2,4-diethyl-3-(ethylsulfanylcarbonyl)-6-phenylpyridine-5-carboxylate, 5-propyl 2,4-diethyl-3-(ethylsulfanylcarbonyl)-6-phenylpyridine-5-carboxylate, 5-propyl 2-ethyl-4-propyl-3-(ethylsulfanylcarbonyl)-6-phenylpyridine-5-carboxylate, 5-hydroxylethyl 2,4diethyl-3-(ethylsulfanylcarbonyl)-6-phenylpyridine-5-carboxylate, 5-ethyl 2,4-diethyl-3-(ethylsulfanylcarbonyl)-6-(m-chlorophenyl)pyridine-5-carboxylate, 5-ethyl 2,4-diethyl-3-(ethylsulfanylcarbonyl)-6-cyclopentylpyridine-5-carboxylate, 5-ethyl 2,4-diethyl-3-propylsulfanylcarbonyl-7-phenylpyridine-5-carboxylate, 5-propyl 2,4-diethyl-3-propylsulfanylcarbonyl-6-(m-chlorophenyl)pyridine-5-carboxylate, 5-ethyl 2-propyl-4-ethyl-3-(ethylsulfanylcarbonyl)-6-phenylpyridine-5-carboxylate, 5-ethyl 2-(2-methoxyethyl)-4-ethyl-3-(ethylsulfanylcarbonyl)-6-phenylpyridine-5-carboxylate, 5-ethyl 2-butyl-4-ethyl-3-(ethylsulfanylcarbonyl)-6-phenylpyridine-5-carboxylate, and 5-ethyl 2-cyclobutyl-4-ethyl-3-(ethylsulfanylcarbonyl)-6-phenylpyridine-5-carboxylate; or a pharmaceutically acceptable salt thereof.
 14. A compound of the formula

or a pharmaceutically acceptable salt thereof; wherein R₂ is a C₁-C₆ alkyl; R₃ is selected from the group consisting of C₁-C₆ alkoxy C₁-C₆ alkylsulfanyl and C₁-C₆ alkylsulfanyl; R₄ is selected from the group consisting of C₁-C₆ alkyl, acetal, formyl, aryl C₂-C₆ alkenyl, and aryl C₂-C₆ alkynyl; R₅ is selected from the group consisting of C₁-C₆ alkyl and aryl C₁-C₆ alkyl; and R₆ is selected from the group consisting of naphthyl and C₃-C₆ cycloalkyl.
 15. The compound of claim 14, wherein R₂ is a C₁-C₆ alkyl; R₃ is selected from the group consisting of C₁-C₆ alkoxy C₁-C₆ alkylsulfanyl and C₁-C₆ alkylsulfanyl; R₄ is selected from the group consisting of C₁-C₆ alkyl, acetal, formyl, aryl C₂-C₆ alkenyl, and aryl C₂-C₆ alkynyl; R₅ is selected from the group consisting of C₁-C₆ alkyl and aryl C₁-C₆ alkyl; and R₆ is C₃-C₆ cycloalkyl; or a pharmaceutically acceptable salt thereof.
 16. The compound of claim 14, wherein R₂ is a C₁-C₆ alkyl; R₃ is selected from the group consisting of C₁-C₆ alkoxy C₁-C₆ alkylsulfanyl, and C₁-C₆ alkylsulfanyl; R₄ is selected from the group consisting of C₁-C₆ alkyl, acetal, formyl, aryl C₂-C₆ alkenyl, and aryl C₂-C₆ alkynyl; R₅ is selected from the group consisting of C₁-C₆ alkyl and aryl C₁-C₆ alkyl; and R₆ is naphthyl; or a pharmaceutically acceptable salt thereof.
 17. A compound selected from the group consisting of 3-ethyl 5-benzyl 2-methyl-4-phenylethynyl-6-cyclopropyl-1,4-(±)-dihydropyridine-3,5-dicarboxylate, 3-ethyl 5-benzyl 2-methyl-4-phenylethynyl-6-cyclobutyl-1,4-(±)-dihydropyridine-3,5-dicarboxylate, 3-ethyl 5-benzyl 2-methyl-4phenylethynyl-6-cyclopentyl-1,4-(±)-dihydropyridine-3,5-dicarboxylate, and 3-ethyl 5-benzyl 2-methyl-4 phenylethynyl-6-cyclohexyl-1,4-(±)-dihydropyridine-3,5-dicarboxylate; or a pharmaceutically acceptable salt thereof.
 18. A compound selected from the group consisting of 3,5-diethyl 2,4-dimethyl-6-phenyl-1,4-(±)-dihydropyrdine-3,5-carboxylate, 3-propyl 5-ethyl-2,4dimethyl-6-phenyl-1,4-(±)-dihydropyridine-3,5-dicarboxylate, 3,5-diethyl 2-methyl-4-ethyl-6-phenyl-1,4-(±)-dihydropyridine-3,5-dicarboxylate, 5-ethyl 2-methyl-4-ethyl-6-phenyl-3-(ethylsulfanylcarbonyl)-1,4-(±)-dihydropyridine-5-carboxylate, 5-ethyl 2-methyl-4-ethyl-6-phenyl-3-(2-methoxyethylsulfanylcarbonyl)-1,4-(±)-dihydropyridine-5-carboxylate, 5-ethyl 2-methyl-4-propyl-6-phenyl-3-(ethylsulfanylcarbonyl)-1,4-(±)-dihydropyridine-5-carboxylate, 5-benzyl 2-methyl-4-ethyl-6-phenyl-3-(ethylsulfanylcarbonyl)-1,4-(±)-dihydropyridine-5-carboxylate, 3,5-diethyl 2-methyl-6-phenyl-4-(dimethoxymethyl)-1,4-(±)-dihydropyridine-3,5-dicarboxylate, 3,5-diethyl 2-ethyl-6-phenyl-4-methyl-1,4-(±)-dihydropyridine-3,5-dicarboxylate, 5-ethyl 2,4-diethyl-6-phenyl-3-(ethylsulfanylcarbonyl)-1,4-(±)-dihydropyridine-5-carboxylate, and 5-ethyl 2-propyl-4-ethyl-6-phenyl-3-(ethylsulfanylcarbonyl)-1,4-(±)-dihydropyridine-5-carboxylate; or a pharmaceutically acceptable salt thereof.
 19. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.
 20. A method of selectively blocking an A₃ adenosine receptor of a mammal comprising administering to said mammal a compound of claim
 1. 21. The method of claim 20, wherein said compound acts as a cerebroprotectant in said mammal.
 22. A method of inhibiting the binding of a ligand to an adenosine receptor of a substrate comprising contacting said substrate with a compound of claim 1 so that said compound binds to said adenosine receptor and inhibits said ligand from binding to said adenosine receptor.
 23. The method of claim 22, wherein said contacting is carried out in vitro.
 24. The method of claim 22, wherein said contacting is carried out in vivo.
 25. A method of characterizing an adenosine receptor site in a substrate comprising contacting said substrate with a compound of claim 1 and evaluating the interaction of said compound and said adenosine receptor.
 26. A pharmaceutical composition comprising a compound of claim 9 and a pharmaceutically acceptable carrier.
 27. A pharmaceutical composition comprising a compound of claim 10 and a pharmaceutically acceptable carrier.
 28. A pharmaceutical composition comprising a compound of claim 11 and a pharmaceutically acceptable carrier.
 29. A pharmaceutical composition comprising a compound of claim 14 and a pharmaceutically acceptable carrier.
 30. A pharmaceutical composition comprising a compound of claim 17 and a pharmaceutically acceptable carrier.
 31. A pharmaceutical composition comprising a compound of claim 18 and a pharmaceutically acceptable carrier.
 32. A method of selectively blocking an A₃ adenosine receptor of a mammal comprising administering to said mammal a compound of claim
 9. 33. A method of selectively blocking an A₃ adenosine receptor of a mammal comprising administering to said mammal a compound of claim
 10. 34. A method of selectively blocking an A₃ adenosine receptor of a mammal comprising administering to said mammal a compound of claim
 11. 35. A method of selectively blocking an A₃ adenosine receptor of a mammal comprising administering to said mammal a compound of claim
 14. 36. A method of selectively blocking an A₃ adenosine receptor of a mammal comprising administering to said mammal a compound of claim
 17. 37. A method of selectively blocking an A₃ adenosine receptor of a mammal comprising administering to said mammal a compound of claim
 18. 38. A method of inhibiting the binding of a ligand to an adenosine receptor of a substrate comprising contacting said substrate with a compound of claim 9 so that said compound binds to said adenosine receptor and inhibits said ligand from binding to said adenosine receptor.
 39. A method of inhibiting the binding of a ligand to an adenosine receptor of a substrate comprising contacting said substrate with a compound of claim 10 so that said compound binds to said adenosine receptor and inhibits said ligand from binding to said adenosine receptor.
 40. A method of characterizing an adenosine receptor site in a substrate comprising contacting said substrate with a compound of claim 9 and evaluating the interaction of said compound and said adenosine receptor. 